Cyclobutyl dihydroquinoline sulfonamide compounds

ABSTRACT

The present invention provides a cyclobutyl dihydroquinoline sulfonamide compound of Formula (I), 
     
       
         
         
             
             
         
       
     
     an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, or a pharmaceutically acceptable salt thereof, that inhibits voltage-gated sodium channels, in particular Nav1.7. The compounds are useful for the treatment of diseases associated with the activity of sodium channels such as pain disorders, cough, and itch. Also provided are pharmaceutical compositions containing the compounds of the present invention. Also further provided is an atropi-selective preparation of said compounds of Formula (I), and intermediate thereof.

RELATED APPLICATION

This application claims priority from U.S. Provisional Application No.63/037,001, having a filing date of Jun. 10, 2020.

FIELD OF THE INVENTION

The present invention provides cyclobutyl dihydroquinoline compoundsthat are inhibitors of voltage-gated sodium channels (Nav), inparticular Nav 1.7, and are useful for the treatment of diseasestreatable by inhibition of sodium channels such as pain disorders. Alsoprovided are pharmaceutical compositions containing compounds of thepresent invention.

BACKGROUND OF THE INVENTION

A 2011 report of the institute of medicine estimates that 100 millionadults in the US, roughly 30% of the population, suffer from chronicpain (C & E News, Bethany Halford, “Changing the Channel”, published3-24). Chronic pain by definition involves abnormal electrical spikingof neurons in the pain pathways: peripheral sensory neurons, spinal cordneurons, neurons in the pain matrix of the brain (e.g., somatosensorycortex, insular cortex, anterior cingular cortex), and/or neurons inbrainstem. Although firing of these neurons is modulated and governed bymany different receptors, enzymes, and growth factors, in most neuronsthe fast upstroke of the electrical spike is produced by entry of sodiumions through voltage-gated sodium channels (Hille B, Ion Channels ofExcitable Membranes. Sinauer Associates, Inc.: Sunderland Mass., 3^(rd)Ed. 2001). There are nine different isoforms of voltage-gated sodiumchannel (Nav 1.1-Nav 1.9), and they have distinct expression patterns intissues including neurons and cardiac and skeletal muscle (Goldin, A. L,“Resurgence of sodium channel research,”Ann Rev Physiol 63:871-894,2001; Wood, J. N. and, Boorman, J. “Voltage-gated sodium channelblockers; target validation and therapeutic potential” Curr. Top Med.Chem. 5:529-537, 2005).

Nav1.1 and Nav1.2 are highly expressed in the brain (Raymond, C. K., etal., J. Biol. Chem. (2004) 279 (44):46234-41) and are vital to normalbrain function. Some loss of function due to Nav 1.1 mutations inhumans, have resulted in epilepsy, presumably as these channels areexpressed in inhibitory neurons (Yu, F. H., et al., Nat. Neuroscience(2006), 9 (9) 1142-1149). Nav1.1 is also expressed in the peripheralnervous system and inhibition of Nav1.1 in the periphery may providerelief of pain. Hence, while inhibiting Nav1.1 may provide use fortreating pain, it may also be undesirable possibly leading to anxietyand over excitability. Nav1.3 is expressed primarily in the fetalcentral nervous system, and expression was found to be upregulated afternerve injury in rats (Haim, B. D., et al., J. Neuroscience (2030)23(26):8881-8892). Nav1.4 is expressed primarily in skeletal muscle.Mutations of the gene and its' product have significant impact on musclefunction, including paralysis (Tamaoka A., Internal Medicine (2003),(9):769-770). Nav1.5 is expressed mainly in cardiac myocytes, includingatria, ventricles, the sino-atrial node, atrioventricular node andcardiac Purkinje fibers. The rapid upstroke of the cardiac actionpotential and the rapid impulse conduction through cardiac tissue is dueto the opening of the Nav1.5 channel Mutations of the Nav1.5 channelhave resulted in arrhythmic syndromes, including QTc prolongation,Brugada syndrome (BS), sudden unexpected nocturnal death syndrome(SUNDS) and sudden infant death syndrome (SIDS) (Liu, H., et al., Am. J.Pharmacogenomics (2003), 3(3):173-179). Nav1.6 is widely distributedvoltage-gated sodium channel expressed throughout the central andperipheral nervous system. Nav1.8 is expressed primarily in sensoryganglia of the peripheral nervous system, such as the dorsal rootganglia. There are no identified Nav1.8 mutations that produce variedpain responses in humans. Nav1.8 differs from most neuronal Nav isotypesin that it is insensitive to inhibition by tetrodotoxin. Nav1.9, similarto Nav1.8, is also a tetrodotoxin insensitive sodium channels expressedprimarily in dorsal root ganglia neurons (Dib-Hajj, S. D., et al., Proc.Natl. Acad. Sci. USA (1998), 95(15):8963-8968).

Recent evidence from several independent genetic studies has shown thatthe tetrodotoxin-sensitive voltage-gated sodium ion channel Nav 1.7(SCN9A) is required to sense pain. Rare genetic forms of severe chronicpain, Primary Erythromelalgia and Paroxysmal Extreme Pain Disorder,result from mutations that increase the activity of Nav 1.7 (FertlemanC. R., Baker M. D., Parker K. A., Moffatt S., et al., “SCN9A mutationsin paroxysmal extreme pain disorder: allelic variants underlie distinctchannel defects and phenotypes,” Neuron 52:767-774, 2006; Yang Y., WangY., Li S, et al., “Mutations in SCN9A, encoding a sodium channel alphasubunit, in patients with primary erythermalgia,” J. Med. Genet.41:171-174, 2004; Drenth J. P. H., to Morsche R. H. M., Guillet G.,Taieb A., et al., “SCN9A mutations define primary erythermalgia as aneuropathic disorder of voltage gated sodium channels,” J InvestDermatol 124:1333-1338). Conversely, two separate clinical studies havedetermined that the root cause of the genetic disorder CongenitalIndifference to Pain (CIP) is a loss of function of Nav 1.7 viamutations that truncate the protein and destroy function (Cox J. J.,Reimann F, Nicholas A. K., et al. “An SCN9A channelopathy causescongenital inability to experience pain,” Nature 444:894-898, 2006;Goldberg Y. P., MacFarlane J., MacDonald M. L., Thompson J., et al.“Loss-of-function mutations in the Nav1.7 gene underlie congenitalindifference to pain in multiple human populations,” Clin Genet71:311-319, 2007). The disorder is inherited in Mendelian recessivemanner with 100% penetrance. The phenotype associated with CIP isextreme: affected individuals are reported to have experienced painlessburns, childbirth, appendicitis, and bone fractures, as well as to haveinsensitivity to clinical measures of pain such as pinprick or tendonpressure. Yet sensory, motor, autonomic, and other measured functionsare normal, with the only reported abnormality being anosmia (inabilityto smell). These studies indicate that among the many possible targetsin the pain pathway, Nav 1.7 governs one or more control points criticalfor pain perception.

Nonselective sodium channel inhibitors such as lidocaine, mexiletine,and carbamazepine show clinical efficacy in chronic pain, includingneuropathic pain, but they are limited in dose and in use, likely due toeffects on sodium channels outside the pain pathway. Lidocaine is alocal anesthetic doctors use for minor surgery. Dentists use novocaine.However, these compounds do not distinguish between the various sodiumchannel subtypes, making them unsuitable for use as systemic painkillers. “If you give a drug that blocks Nav1.7 but also blocks Nav1.5,the patient will die of heart failure,” says Glenn F. King, a professorat Australia's University of Queensland who studies venoms that blockion channels. “It will be a completely painless death, but the patientwill die nonetheless.” Thus, selectivity for Nav1.7 is desired,particularly over Nav1.5. Researchers have tailored their efforts tofind a molecule that inhibitors or block the activity of only Nav1.7. Tocompound this problem, the identity, every location, every functionand/or the tertiary structures of each subtype of voltage gated sodiumchannel proteins are not known or completely understood.

Consequently, a number of researchers are attempting to identify smallmolecule inhibitors of Nav1.7. For example, Chafeev et al disclosespiro-oxindole compound for the treatment and/or prevention of sodiumchannel-mediated diseases, such as pain, in U.S. Pat. No. 8,101,647.International Publications WO 2013/134518 and WO 2014/201206 disclosesulfonamide derivatives which are different from the sulfonamidederivatives of the present invention. Thus, there is a need to identifyNav1.7 inhibitors selective over at least Nav1.5 to treat pain. Thepresent invention provides compounds that are selective inhibitors ofNav 1.7. over at least Nav1.5.

SUMMARY OF THE INVENTION

In embodiment 1, the present invention provides a compound of Formula(I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof,

wherein:

R¹ is a saturated or partially-saturated 4-membered monocyclic ring; ora 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring;wherein said monocyclic ring or bicyclic ring contains 0, 1, 2 or 3 Natoms and 0, 1, or 2 atoms selected from O and S; and wherein saidmonocyclic ring or bicyclic ring is substituted by 0, 1, 2 or 3 R^(1a)groups selected from hydroxy, halo, C₁₋₈alk, C₁₋₈haloalk, —O—C₁₋₄alk,—O—C₁₋₈haloalk, —C(═O)C₁₋₄alk, —O—C(═O)C₁₋₄alk, —NH₂, —NHC₁₋₄alk, or—N(C₁₋₄alk)C₁₋₄alk;

R² is H, halo, C₁₋₆alk, or C₁₋₆haloalk;

R³ is C₁₋₆alk, C₁₋₆haloalk, —O—C₁₋₆alk, or CN;

R⁴ is a 5- to 6-membered heteroaryl;

Each of R⁶ and R⁷ is hydrogen; and

Each of R^(5a); R^(5b); R^(5b); R^(5d); and R^(5e) is independentlyhydrogen or halo.

In sub-embodiment 1a of embodiment 1, the compound of Formula (I) has asub-Formula of (Ia):

wherein R_(1a) is fluoro, chloro, methyl, —O—CF₃, or CF₃.

In a more preferred sub embodiment 1a of embodiment 1, R^(1a) is CF₃ or—O—CF₃; R² is H, F, or methyl; and R⁴ is isoxazolyl or pyridazinyl.

In a most preferred sub embodiment 1a of embodiment 1, R^(1a) is CF₃; R²is F; and R⁴ is isoxazolyl.

In sub-embodiment 1b of embodiment 1, the compound of Formula (I) has asub-Formula of (Ib):

wherein each R^(1a) is fluoro or CF₃.

In a more preferred sub embodiment 1b of embodiment 1, each R^(1a) is F;R² is F or Cl; and R⁴ is isoxazolyl.

In a most preferred sub embodiment 1b of embodiment 1, each R^(1a) is F;R² is F; and R⁴ is isoxazolyl.

In sub-embodiment 1c of embodiment 1, the compound of Formula (I) has asub-Formula of (Ic):

wherein R^(1a) is CF₃.

In a more preferred sub embodiment 1c of embodiment 1, R^(1a) is CF₃; R²is F; and R⁴ is isoxazolyl or pyrimidyl.

In a most preferred sub embodiment 1c of embodiment 1, R^(1a) is CF₃; R²is F; and R⁴ is isoxazolyl.

In embodiment 2, the present invention provides compounds of Formula(I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein theR^(1a) group is selected from halo, C₁₋₈alk, —O—C₁₋₄alk, or C₁₋₈haloalk,wherein said C₁₋₈haloalk is C₁₋₈fluoroalkyl.

In embodiment 3, the present invention provides compounds of Formula(I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein R¹ is acyclobutyl ring; or a 5-, or 6-membered bicyclic ring; wherein saidcyclobutyl ring or bicyclic ring contains 0 N, O, and S atoms; andwherein said cyclobutyl ring or bicyclic ring is substituted by 1, 2 or3 R^(1a) groups selected from F, —CF₃, —O—CF₃, or —C(CH₃)₃.

In embodiment 4, the present invention provides compounds of Formula(I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein R¹ is acyclobutyl ring or bicyclo[1.1.1]pentan-1-yl ring; wherein each ring issubstituted by 1 or 2 F or —CF₃.

In embodiment 5, the present invention provides compounds of Formula(I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein R¹ is acyclobutyl ring substituted by 1 or 2 F or —CF₃.

In sub-embodiment 5a of embodiment 5, the compound of Formula (I) hasthe above sub-Formula of (Ia) and R^(1a) is F.

In sub-embodiment 5b of embodiment 5, the compound of Formula (I) hasthe above sub-Formula of (Ib) and R^(1a) is —CF₃.

In sub-embodiment 5c of embodiment 5, R¹ is a cyclobutyl ringsubstituted by 1 —CF₃.

In sub-embodiment 5d of embodiment 5, R¹ is a cyclobutyl ringsubstituted by 1 or 2 F.

In sub-embodiment 5c of embodiment 5, the compound of Formula (I) hasthe above sub-Formula of (Ic) and R^(1a) is —CF₃.

In embodiment 6, the present invention provides compounds of Formula(I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein R¹ is abicyclo[1.1.1]pentan-1-yl ring substituted by 1 or 2 F or —CF₃.

In embodiment 7, the present invention provides compounds of Formula(I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein R² is H,fluoro, chloro, methyl, CF₃, CHF₂, or CH₂F. In sub embodiment 7a ofembodiment 7, R² is fluoro.

In embodiment 8, the present invention provides compounds of Formula(I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein R² is H,fluoro, chloro, or methyl.

In embodiment 9, the present invention provides compounds of Formula(I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein R² is Hor fluoro.

In embodiment 10, the present invention provides compounds of Formula(I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein R³ ismethoxy.

In embodiment 11, the present invention provides compounds of Formula(I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein R⁴ is a5-membered heteroaryl.

In embodiment 12, the present invention provides compounds of Formula(I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein R⁴ is a6-membered heteroaryl.

In embodiment 13, the present invention provides compounds of Formula(I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein R⁴ isisoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl, orpyrimidinyl.

In a sub embodiment of embodiment 13a of embodiment 13, R⁴ isisoxazolyl, pyridazinyl, or pyrimidyl.

In another sub embodiment 13b of embodiment 13, R⁴ is isoxazolyl.

In embodiment 14a, the present invention provides compounds of Formula(I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein each ofR^(5a); R^(5b); R^(5c); R^(5d); and R^(5e) is hydrogen.

In embodiment 14b, the present invention provides compounds of Formula(I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein R^(5a)is F; and each of R^(5b); R^(5c); R^(5d); and R^(5e) is hydrogen.

In embodiment 14c, the present invention provides compounds of Formula(I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein R^(5c)is F; and each of R^(5a); R^(5b); R^(5d); and R^(5e) is hydrogen.

In embodiment 15, the present invention provides compounds of Formula(I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein saidcompound of Formula (I) is selected from compounds of Formula (Ia),(Ib), or (Ic):

wherein each R^(1a) in said compounds of Formula (Ia), (Ib), or (Ic) isindependently fluoro, chloro, methyl, —O—CF₃, or CF₃.

In embodiment 16, the present invention provides compounds of Formula(I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein saidcompound of Formula (I) is a compound of Formula (Ia); wherein R^(1a) isCF₃; the cyclobutyl ring is a trans isomer; and R⁴ is isoxazolyl,pyridazinyl, thiazolyl, thiadiazolyl, or oxazolyl.

In embodiment 16a, said compound of Formula (I) is a compound of Formula(Ia); wherein R^(1a) is cis CF₃; the cyclobutyl ring is a cis isomer; R²is F; and R⁴ is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, oroxazolyl.

In embodiment 16b, said compound of Formula (I) is a compound of Formula(Ib); wherein each R^(1a) is fluoro; R² is F; and R⁴ is isoxazolyl,pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl.

In embodiment 16c, said compound of Formula (I) is a compound of Formula(Ib); wherein each R^(1a) is fluoro; R^(5a) is F; and R⁴ is isoxazolyl,pyridazinyl, thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl.

In embodiment 16d, said compound of Formula (I) is a compound of Formula(Ic); wherein each R^(1a) is CF₃.

In embodiment 17, the present invention provides compounds of Formula(I), an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein thecompound is selected from:

1)(M)-1-(4-(3-(tert-Butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

2)1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

3)(P)-1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

4)(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

5)(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

6)cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

7)trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

8)trans-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

9)cis-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

10)cis-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

11)trans-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

12) cis-(P)-1-(5-chloro-2-methoxy-4-41 S,3S)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

13) trans-(P)-1-(5-chloro-2-methoxy-4-((1S,3S)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

14)(P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

15)trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

16)cis-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

17)trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

18)(P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

19)trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;

20)trans-(P)—N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

21)(P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

22)(P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

23)(P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;

24)(P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

25)(P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

26)(P)-1-(4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

27)(P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

28)(P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

29)(P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

30)(P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;

31)(P)-1-(4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;

32)(P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

33)(P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;

34)(P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

35)trans-(P)—N-(isoxazol-3-yl)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

36)trans-(P)-1-(2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

37)trans-(P)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

38)trans-(P)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;

39)trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;

40)(P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

41)(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

42)(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

43)(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

44)cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

45)trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

46)trans-(P)-5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

47)(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

48)(P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;or

-   -   49) trans        (P)-1-(5-chloro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

In embodiment 18, the present invention provides a compound of Formula(I), having sub-Formula of (Ia):

an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein thecompound is selected from:

1)cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

2)trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

3)cis-(P)-1-(5-chloro-2-methoxy-4-((1S,3S)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

4)trans-(P)-1-(5-chloro-2-methoxy-4-((1S,3S)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

5)trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

6)trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;

7)trans-(P)—N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

8)trans-(P)-1-(2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

9)trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;

10)(P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

11)(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

12)cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

13)trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

14)trans-(P)-5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;or

15) trans(P)-1-(5-chloro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)

16) phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

In sub-embodiment 18a of embodiment 18, the present invention provides acompound of Formula (I), having the above sub-Formula of (Ia), anenantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof,or a pharmaceutically acceptable salt thereof, wherein the compound isselected from:

1)trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

2)trans-(P)—N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

3)trans-(P)-1-(2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;

4)trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;

5)trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;or 6)trans-(P)-5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

In sub-embodiment 18b of embodiment 18, the present invention provides acompound of Formula (I), having the above sub-Formula of (Ia), anenantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof,or a pharmaceutically acceptable salt thereof, wherein the compound istrans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

In sub-embodiment 18c of embodiment 18, the present invention provides acompound of Formula (I), having the above sub-Formula of (Ia), anenantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof,or a pharmaceutically acceptable salt thereof, which istrans-(P)—N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

In sub-embodiment 18d of embodiment 18, the present invention provides acompound of Formula (I), having the above sub-Formula of (Ia), anenantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof,or a pharmaceutically acceptable salt thereof, which istrans-(P)-1-(2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide.

In sub-embodiment 18e of embodiment 18, the present invention provides acompound of Formula (I), having the above sub-Formula of (Ia), anenantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof,or a pharmaceutically acceptable salt thereof, which istrans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide.

In sub-embodiment 18f of embodiment 18, the present invention provides acompound of Formula (I), having the above sub-Formula of (Ia), anenantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof,or a pharmaceutically acceptable salt thereof, which istrans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

In sub-embodiment 18g of embodiment 18, the present invention provides acompound of Formula (I), having the above sub-Formula of (Ia), anenantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof,or a pharmaceutically acceptable salt thereof, which istrans-(P)-5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

In embodiment 19, the present invention provides a compound of Formula(I), having sub-Formula of (Ib):

an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, which isselected from:

1)(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

2)(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

3)trans-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

4)cis-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

5)cis-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

6)trans-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

7)(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;or

8)(P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

In sub-embodiment 19a of embodiment 19 the present invention provides acompound of Formula (I), having the above sub-Formula of (Ib), anenantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof,or a pharmaceutically acceptable salt thereof, which is selected from:

1)(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

2)trans-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;

3)cis-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;or 4)trans-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

In sub-embodiment 19b of embodiment 19, the present invention provides acompound of Formula (I), having the above sub-Formula of (Ib), anenantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof,or a pharmaceutically acceptable salt thereof, which is(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

In sub-embodiment 19c of embodiment 19, the present invention provides acompound of Formula (I), having the above sub-Formula of (Ib), anenantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof,or a pharmaceutically acceptable salt thereof, which istrans-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

In sub-embodiment 19d of embodiment 19, the present invention provides acompound of Formula (I), having the above sub-Formula of (Ib), anenantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof,or a pharmaceutically acceptable salt thereof, which iscis-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

In sub-embodiment 19e of embodiment 19, the present invention provides acompound of Formula (I), having the above sub-Formula of (Ib), anenantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof,or a pharmaceutically acceptable salt thereof, which istrans-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

In embodiment 20, the present invention provides a compound of Formula(I) having a sub-Formula of (Ic):

an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, which isselected from:

(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;or

(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide.

In sub-embodiment 20a of embodiment 20, the present invention provides acompound of Formula (I), having the above sub-Formula of (Ic), anenantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof,or a pharmaceutically acceptable salt thereof, which is(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.

In sub-embodiment 20b of embodiment 20, the present invention provides acompound of Formula (I), having the above sub-Formula of (Ic), anenantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof,or a pharmaceutically acceptable salt thereof, which is(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide.

In embodiment 21, the present invention provides a P atropisomer of eachindividual compound, independently, or a mixture thereof, orpharmaceutically acceptable salts thereof, recited in embodiments 18,19, and 20, or any sub-embodiment thereof.

In embodiment 22, the present invention provides an M atropisomer ofeach individual compound, independently, or a mixture thereof, orpharmaceutically acceptable salts thereof, recited in embodiments 18,19, and 20, or any sub-embodiment thereof.

In embodiment 23, the present invention provides pharmaceuticalcompositions comprising a compound, an enantiomer, diastereoisomer,atropisomer thereof, or a mixture thereof, or pharmaceuticallyacceptable salts thereof, in accordance with any one of embodiments 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, or any sub embodiment thereof, and a pharmaceutically acceptableexcipient.

In embodiment 24, the present invention provides methods of treatingpain, cough, or itch, the methods comprising administering to a patientin need thereof a therapeutically effective amount of a compound, anenantiomer, diastereoisomer, atropisomer thereof, or a mixture thereof,or pharmaceutically acceptable salts thereof, in accordance with any oneof embodiments 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, or any sub embodiment thereof.

In embodiment 25, the present invention provides methods of embodiment24 wherein the pain is selected from chronic pain, acute pain,neuropathic pain, pain associated with rheumatoid arthritis, painassociated with osteoarthritis, pain associated with cancer, peripheraldiabetic neuropathy, and neuropathic low back pain.

In embodiment 26, the present invention provides methods of embodiment24 wherein the cough is selected from post viral cough, viral cough, oracute viral cough. See Dib-Hajj. et. al., “The Nav1.7 sodium channel;from molecule to man”, Nature Reviews Neuroscience (2013), 14, 49-62.

In embodiment 27, the present invention provides a method of preparationof an intermediate compound used in the preparation of a compound ofFormula (I), having the Formula (A):

wherein R is halo;comprising:

-   -   1) reacting a trans olefin compound of Formula (B):

wherein R is halo; and R¹ is C₁-C₆alkyl;with a UV light or near UV light; to form a cis olefin compound (C); and

-   -   2) reacting said compound (C) with a chiral acid in an organic        solvent to form said compound of Formula (A).

In embodiment 28, the present invention provides a method of embodiment27, wherein said chiral acid is a phosphorus chiral acid.

In embodiment 29, the present invention provides a method of embodiment27, wherein said chiral acid is (S)-TRIP having the Formula:

In embodiment 30, the present invention provides a method of embodiment27, wherein said organic solvent is dichloromethane.

In embodiment 31, the present invention provides a method of embodiment27, wherein said R is bromo.

In embodiment 32, the present invention provides a method of embodiment27, wherein said R¹ is ethyl; wherein the compound of Formula (B) hasthe formula:

In embodiment 33, the present invention provides a method of embodiment27, wherein in reaction (2), a P atropisomer of said compound of Formula(A) is selectively formed.

In embodiment 34, the present invention provides a method of embodiment27, wherein said compound of Formula (A) is used as an intermediatecompound in preparation of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

R¹ is a saturated or partially-saturated 4-membered monocyclic ring; ora 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring;wherein said monocyclic ring or bicyclic ring contains 0, 1, 2 or 3 Natoms and 0, 1, or 2 atoms selected from O and S; and wherein saidmonocyclic ring or bicyclic ring is substituted by 0, 1, 2 or 3 R^(1a)groups selected from hydroxy, halo, C₁₋₈alk, C₁₋₈haloalk, —O—C₁₋₄alk,—O—C₁₋₈haloalk, —C(═O)C₁₋₄alk, —O—C(═O)C₁₋₄alk, —NH₂, —NHC₁₋₄alk, or—N(C₁₋₄alk)C₁₋₄alk;

R² is H, halo, C₁₋₆alk, or C₁₋₆haloalk;

R³ is C₁₋₆alk, C₁₋₆haloalk, —O—C₁₋₆alk, or CN;

R⁴ is a 5- to 6-membered heteroaryl;

Each of R⁶ and 127 is hydrogen; and

Each of R^(5a); R^(5b); R^(5c); R^(5d); and R^(5e) is independentlyhydrogen or halo; and

Wherein a P atropisomer of said compound of Formula (I) is selectivelyformed.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds of Formula (I), as definedabove, an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or pharmaceutically acceptable salts thereof. The presentinvention also provides pharmaceutical compositions comprising acompound of Formula (I), an enantiomer, diastereoisomer, atropisomerthereof, or a mixture thereof, or pharmaceutically acceptable saltsthereof, and methods of treating diseases and/or conditions, such aspain, using compounds of Formula (I), an enantiomer, diastereoisomer,atropisomer thereof, or a mixture thereof, or pharmaceuticallyacceptable salts thereof.

The term “C_(α,β)alk” means an alkyl group comprising a minimum of α anda maximum of β carbon atoms in a branched or linear relationship or anycombination of the two, wherein α and β represent integers. Adesignation of C₀alk indicates a direct bond. Examples of C₁₋₆alkinclude, but are not limited to, the following:

The term “halo” or “halogen” means a halogen atoms selected from F, Cl,Br or I.

The term “C_(α-β)haloalk” means an alk group, as defined herein, inwhich at least one of the hydrogen atoms has been replaced with a haloatom, as defined herein. Common C_(α-β)haloalk groups are C₁₋₃fluoroalk.An example of a common C₁₋₃fluoroalk group is —CF₃.

The term “heteroatom” as used herein means an oxygen, nitrogen or sulfuratom.

The term “monocyclic ring” as used herein means a group that featuresone single ring. A monocyclic ring can be carbocyclic (all of the ringatoms are carbons), or heterocyclic (the rings atoms include at least 1heteroatom, for example, 1, 2 or 3 heteroatoms, such as N, O, or S, inaddition to carbon atoms). Examples of monocyclic rings include, but arenot limited to: cyclobutyl, cyclopentyl, or cyclohexyl.

The term “bicyclic ring” as used herein means a group that features twojoined rings. A bicyclic ring can be carbocyclic (all of the ring atomsare carbons), or heterocyclic (the rings atoms include at least oneheteroatom, for example, 1, 2 or 3 heteroatoms, such as N, O, or S, inaddition to carbon atoms). The two rings can both be aliphatic (e.g.decalin and norbornane), or can be aromatic (e.g. naphthalene), or acombination of aliphatic and aromatic (e.g. tetralin). Bicyclic ringsinclude (a) spirocyclic compounds, wherein the two rings share only onesingle atom, the Spiro atom, which is usually a quaternary carbon.Examples of spirocyclic compound include, but are not limited to:

or

(b) fused bicyclic compounds, wherein two rings share two adjacentatoms, in other words, the rings share one covalent bond. i.e. thebridgehead atoms are directly connected (e.g. α-thujene and decalin).Examples of fused bicyclic rings include, but are not limited to:

and(c) bridged bicyclic compounds, wherein the two rings share three ormore atoms, separating the two bridgehead atoms by a bridge containingat least one atom. For example, norbornane, also known asbicyclo[2.2.1]heptane, can be thought of as a pair of cyclopentane ringseach sharing three of their five carbon atoms. Examples of bridgedbicyclic rings include, but are not limited to:

The term “aryl” means a cyclic, aromatic hydrocarbon. Examples of arylgroups include phenyl and naphthyl. Common aryl groups are six tothirteen membered rings.

The term “heteroaryl” means a cyclic, aromatic hydrocarbon in which oneor more carbon atoms of an aryl group have been replaced with aheteroatom. If the heteroaryl group contains more than one heteroatom,the heteroatoms may be the same or different. Examples of heteroarylgroups include pyridyl, pyrimidinyl, imidazolyl, thienyl, furyl,pyrazinyl, pyrrolyl, indolyl, triazolyl, pyridazinyl, indazolyl,purinyl, quinolizinyl, isoquinolyl, quinolyl, naphthyridinyl,quinoxalinyl, isothiazolyl and benzo[b]thienyl. Common heteroaryl groupsare five to thirteen membered rings that contain from 1 to 4heteroatoms. Heteroaryl groups that are five and six membered rings thatcontain 1 to 3 heteroatoms are particularly common.

The term “saturated, partially-saturated or unsaturated” includessubstituents saturated with hydrogens, substituents completelyunsaturated with hydrogens and substituents partially saturated withhydrogens.

The term “pharmaceutically acceptable salt” means a salt prepared byconventional means, and are well known by those skilled in the art. The“pharmacologically acceptable salts” include basic salts of inorganicand organic acids, including but not limited to hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaricacid, citric acid, lactic acid, fumaric acid, succinic acid, maleicacid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid andthe like. For additional examples of “pharmacologically acceptablesalts,” and Berge et al., J. Pharm. Sci. 66:1 (1977).

The term “substituted” means that a hydrogen atom on a molecule or groupis replaced with a group or atom other than hydrogen. Typicalsubstituents include: halogen, C₁₋₈alkyl, hydroxyl, C₁₋₈alkoxy,NR^(x)R^(x), nitro, cyano, halo or perhaloC₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, SR^(x), —S(═O)₂R^(x), C(═O)OR^(x), C(═O)R^(x), wherein eachR^(x) is independently hydrogen or C₁-C₈ alkyl. It is noted that whenthe substituent is NR^(x)R^(x), the R^(x) groups may be joined togetherwith the nitrogen atom to form a ring.

A group or atom that replaces a hydrogen atom is also called asubstituent.

Any particular molecule or group can have one or more substituentdepending on the number of hydrogen atoms that can be replaced.

The term “unsubstituted” means a hydrogen atom on a molecule or group.

The symbol “—” represents a covalent bond and can also be used in aradical group to indicate the point of attachment to another group. Inchemical structures, the symbol is commonly used to represent a methylgroup in a molecule.

The term “leaving group” generally refers to groups readily displaceableby a nucleophile, such as an amine, a thiol or an alcohol nucleophile,or by metallic agent such as boronic acids or boronates under transitionmetal catalyzed coupling conditions. Such leaving groups are well knownin the art. Examples of such leaving groups include, but are not limitedto, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates,tosylates and the like. Preferred leaving groups are indicated hereinwhere appropriate.

The term “protecting group” generally refers to groups well known in theart which are used to prevent selected reactive groups, such as carboxy,amino, hydroxy, mercapto and the like, from undergoing undesiredreactions, such as nucleophilic, electrophilic, oxidation, reduction andthe like. Preferred protecting groups are indicated herein whereappropriate. Examples of amino protecting groups include, but are notlimited to, aralkyl, substituted aralkyl, cycloalkenylalkyl andsubstituted cycloalkenyl alkyl, allyl, substituted allyl, acyl,alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples ofaralkyl include, but are not limited to, benzyl, ortho-methylbenzyl,trityl and benzhydryl, which can be optionally substituted with halogen,alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts,such as phosphonium and ammonium salts. Examples of aryl groups includephenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl),phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl orsubstituted cycloalkylenylalkyl radicals, preferably have 6-10 carbonatoms, include, but are not limited to, cyclohexenyl methyl and thelike. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups includebenzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl,substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloro acetyl,phthaloyl and the like. A mixture of protecting groups can be used toprotect the same amino group, such as a primary amino group can beprotected by both an aralkyl group and an aralkoxycarbonyl group. Aminoprotecting groups can also form a heterocyclic ring with the nitrogen towhich they are attached, for example, 1,2-bis(methylene)benzene,phthalimidyl, succinimidyl, maleimidyl and the like and where theseheterocyclic groups can further include adjoining aryl and cycloalkylrings. In addition, the heterocyclic groups can be mono-, di- ortri-substituted, such as nitrophthalimidyl. Amino groups may also beprotected against undesired reactions, such as oxidation, through theformation of an addition salt, such as hydrochloride, toluenesulfonicacid, trifluoroacetic acid and the like. Many of the amino protectinggroups are also suitable for protecting carboxy, hydroxy and mercaptogroups. For example, aralkyl groups. Alkyl groups are also suitablegroups for protecting hydroxy and mercapto groups, such as tert-butyl.

Protecting groups are removed under conditions which will not affect theremaining portion of the molecule. These methods are well known in theart and include acid hydrolysis, hydrogenolysis and the like. Apreferred method involves removal of a protecting group, such as removalof a benzyloxycarbonyl group by hydrogenolysis utilizing palladium oncarbon in a suitable solvent system such as an alcohol, acetic acid, andthe like or mixtures thereof. A tert-butoxycarbonyl protecting group canbe removed utilizing an inorganic or organic acid, such as HCl ortrifluoroacetic acid, in a suitable solvent system, such as dioxane ormethylene chloride. The resulting amino salt can readily be neutralizedto yield the free amine. Carboxy protecting group, such as methyl,ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can beremoved under hydrolysis and hydrogenolysis conditions well known tothose skilled in the art.

Prodrugs of the compounds of this invention are also contemplated bythis invention. A prodrug is an active or inactive compound that ismodified chemically through in vivo physiological action, such ashydrolysis, metabolism and the like, into a compound of this inventionfollowing administration of the prodrug to a patient. The suitabilityand techniques involved in making and using prodrugs are well known bythose skilled in the art. For a general discussion of prodrugs involvingesters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) andBundgaard Design of Prodrugs, Elsevier (1985). Examples of a maskedcarboxylate anion include a variety of esters, such as alkyl (forexample, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl(for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (forexample, pivaloyloxymethyl). Amines have been masked asarylcarbonyloxymethyl substituted derivatives which are cleaved byesterases in vivo releasing the free drug and formaldehyde (Bundgaard J.Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, suchas imidazole, imide, indole and the like, have been masked withN-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloanand Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acidprodrugs, their preparation and use.

The term “therapeutically effective amount” means an amount of acompound that ameliorates, attenuates or eliminates one or more symptomof a particular disease or condition, or prevents or delays the onset ofone of more symptoms of a particular disease or condition.

The term “patient” means animals, such as dogs, cats, cows, horses,sheep and humans. Particular patients are mammals. The term patientincludes males and females.

The term “pharmaceutically acceptable” means that the referencedsubstance, such as a compound of Formula (I), or a salt of a compound ofFormula (I), or a formulation containing a compound of Formula (I), or aparticular excipient, are suitable for administration to a patient.

The terms “treating”, “treat” or “treatment” and the like includepreventative (e.g., prophylactic) and palliative treatment.

The term “excipient” means any pharmaceutically acceptable additive,carrier, diluent, adjuvant, or other ingredient, other than the activepharmaceutical ingredient (API), which is typically included forformulation and/or administration to a patient.

The compounds of the present invention are administered to a patient ina therapeutically effective amount. The compounds can be administeredalone or as part of a pharmaceutically acceptable composition orformulation. In addition, the compounds or compositions can beadministered all at once, as for example, by a bolus injection, multipletimes, such as by a series of tablets, or delivered substantiallyuniformly over a period of time, as for example, using transdermaldelivery. It is also noted that the dose of the compound can be variedover time.

In addition, the compounds of the present invention can be administeredalone, in combination with other compounds of the present invention, orwith other pharmaceutically active compounds. The other pharmaceuticallyactive compounds can be intended to treat the same disease or conditionas the compounds of the present invention or a different disease orcondition. If the patient is to receive or is receiving multiplepharmaceutically active compounds, the compounds can be administeredsimultaneously, or sequentially. For example, in the case of tablets,the active compounds may be found in one tablet or in separate tablets,which can be administered at once or sequentially in any order. Inaddition, it should be recognized that the compositions may be differentforms. For example, one or more compound may be delivered by a tablet,while another is administered by injection or orally as syrup. Allcombinations, delivery methods and administration sequences arecontemplated.

The compounds of the present invention may be used in the manufacture ofa medicament for the treatment of a disease and/or condition mediated byNav 1.7, such as pain, chronic cough or itch.

Pain is typically divided into primary types: chronic and acute painbased on the duration of the pain. Typically, chronic pain lasts forlonger than 3 months. Examples of chronic pain include pain associatedwith rheumatoid arthritis, osteoarthritis, lumbosacral radiculopathy orcancer. Chronic pain also includes idiopathic pain, which is pain thathas no identified cause. An example of idiopathic pain is fibromyalgia.

Another type of pain is nociceptive pain. Nociceptive pain is caused bystimulation of peripheral nerve fibers that respond to highly noxiousevents such as thermal, mechanical or chemical stimuli.

Still another type of pain is neuropathic pain. Neuropathic pain is painthat is caused by damage or disease affecting a part of the nervoussystem. Phantom limb pain is a type of neuropathic pain. In phantom limbpain, the body detects pain from a part of a body that no longer exists.For example, a person who has had a leg amputated may feel leg pain eventhough the leg no longer exists.

In one embodiment of the methods of treatment provided by the presentinvention using the compounds of Formula (I), or pharmaceuticallyacceptable salts thereof, the disease is chronic pain. In anotheraspect, the chronic pain is associated with, but are not limited to,post-herpetic neuralgia (shingles), rheumatoid arthritis,osteoarthritis, diabetic neuropathy, complex regional pain syndrome(CRPS), cancer or chemotherapy-induced pain, chronic back pain, phantomlimb pain, trigeminal neuralgia, HIV-induced neuropathy, clusterheadache disorders, and migraine, primary erythromelalgia, andparoxysmal extreme pain disorder. Other indications for Nav 1.7inhibitors include, but are not limited to, depression (Morinville etal., J Comp Neurol., 504:680-689 (2007)), bipolar and other CNSdisorders (Ettinger and Argoff, Neurotherapeutics, 4:75-83 (2007)),epilepsy: ibid., and Gonzalez, Termin, Wilson, Methods and Principles inMedicinal Chemistry, 29:168-192 (2006)), multiple sclerosis (Waxman,Nature Neurosci. 7:932-941 (2006)), Parkinson's (Do and Bean, Neuron39:109-120 (2003); Puopolo et al., J. Neurosci. 27:645-656 (2007)),restless legs syndrome, ataxia, tremor, muscle weakness, dystonia,tetanus (Hamann M., et. al., Exp. Neurol. 184(2):830-838, 2003),anxiety, depression: McKinney B. C, et. al., Genes Brain Behav.7(6):629-638, 2008), learning and memory, cognition (Woodruff-Pak D. S.,et. al., Behav. Neurosci. 120(2):229-240, 2006), cardiac arrhythmia andfibrillation, contractility, congestive heart failure, sick sinussyndrome (Haufe V., et. al., J. Mol. Cell Cardiol. 42(3):469-477, 2007),schizophrenia, neuroprotection after stroke, drug and alcohol abuse(Johannessen L. C., CNS Drugs 22(1)27-47, 2008), Alzheimer's (Kim D. Y.,et. al., Nat. Cell. Biol. 9(7):755-764, 2007), and cancer (Gillet L.,et. al., J. Biol Chem 2009, Jan. 28 (epub)).

Another aspect of the invention relates to a method of treating acuteand/or chronic inflammatory and neuropathic pain, dental pain, generalheadache, migraine, cluster headache, mixed-vascular and non-vascularsyndromes, tension headache, general inflammation, arthritis, rheumaticdiseases, rheumatoid arthritis, osteoarthritis, inflammatory boweldisorders, inflammatory eye disorders, inflammatory or unstable bladderdisorders, psoriasis, skin complaints with inflammatory components,chronic inflammatory conditions, inflammatory pain and associatedhyperalgesia and allodynia, neuropathic pain and associated hyperalgesiaand allodynia, diabetic neuropathy pain, causalgia, sympatheticallymaintained pain, deafferentation pain syndromes, asthma, epithelialtissue damage or dysfunction, herpes simplex, disturbances of visceralmotility at respiratory, genitourinary, gastrointestinal or vascularregions, wounds, burns, allergic skin reactions, pruritus, vitiligo,general gastrointestinal disorders, gastric ulceration, duodenal ulcers,diarrhea, gastric lesions induced by necrotising agents, hair growth,vasomotor or allergic rhinitis, bronchial disorders or bladderdisorders, comprising the step of administering a compound according tothe present invention. A preferred type of pain to be treated is chronicneuropathic pain. Another preferred type of pain to be treated ischronic inflammatory pain.

In another aspect of the invention, the compounds of the presentinvention can be used in combination with other compounds that are usedto treat pain. Examples of such other compounds include, but are notlimited to aspirin, celecoxib, hydrocodone, oxycodone, codeine,fentanyl, ibuprofen, ketoprofen, naproxen, acetaminophen, gabapentin andpregabalin. Examples of classes of medicines that contain compounds thatcan be used in combination with the compounds of the present inventioninclude non-steroidal anti-inflammatory compounds (NSAIDS), steroidalcompounds, cyclooxygenase inhibitors and opioid analgesics.

The compounds of the present invention may also be used to treatdiabetes, obesity and/or to facilitate weight loss.

The compounds of the present invention may be used in combination withother pharmaceutically active compounds. It is noted that the term“pharmaceutically active compounds” can include biologics, such asproteins, antibodies and peptibodies.

Since one aspect of the present invention contemplates the treatment ofthe disease/conditions with a combination of pharmaceutically activecompounds that may be administered separately, the invention furtherrelates to combining separate pharmaceutical compositions in kit form.The kit comprises two separate pharmaceutical compositions: a compoundof the present invention, and a second pharmaceutical compound. The kitcomprises a container for containing the separate compositions such as adivided bottle or a divided foil packet. Additional examples ofcontainers include syringes, boxes and bags. Typically, the kitcomprises directions for the use of the separate components. The kitform is particularly advantageous when the separate components arepreferably administered in different dosage forms (e.g., oral andparenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing physician or veterinarian.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. Preferably the strength of the sheet is such that the tablets orcapsules can be removed from the blister pack by manually applyingpressure on the recesses whereby an opening is formed in the sheet atthe place of the recess. The tablet or capsule can then be removed bysaid opening.

It may be desirable to provide a memory aid on the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, . . . etc. . . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several pills or capsules to betaken on a given day. Also, a daily dose of a compound of the presentinvention can consist of one tablet or capsule, while a daily dose ofthe second compound can consist of several tablets or capsules and viceversa. The memory aid should reflect this and aid in correctadministration of the active agents.

In another specific embodiment of the invention, a dispenser designed todispense the daily doses one at a time in the order of their intendeduse is provided. Preferably, the dispenser is equipped with amemory-aid, so as to further facilitate compliance with the regimen. Anexample of such a memory-aid is a mechanical counter which indicates thenumber of daily doses that has been dispensed. Another example of such amemory-aid is a battery-powered micro-chip memory coupled with a liquidcrystal readout, or audible reminder signal which, for example, readsout the date that the last daily dose has been taken and/or reminds onewhen the next dose is to be taken.

The compounds of the present invention and other pharmaceutically activecompounds, if desired, can be administered to a patient either orally,rectally, parenterally, (for example, intravenously, intramuscularly, orsubcutaneously) intracisternally, intravaginally, intraperitoneally,intravesically, locally (for example, powders, ointments or drops), oras a buccal or nasal spray. All methods that are used by those skilledin the art to administer a pharmaceutically active agent arecontemplated.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions, or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents,solvents, or vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispersing agents. Microorganism contaminationcan be prevented by adding various antibacterial and antifungal agents,for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.It may also be desirable to include isotonic agents, for example,sugars, sodium chloride, and the like. Prolonged absorption ofinjectable pharmaceutical compositions can be brought about by the useof agents delaying absorption, for example, aluminum monostearate andgelatin.

Solid dosage forms for oral administration include capsules, tablets,powders, and granules. In such solid dosage forms, the active compoundis admixed with at least one inert customary excipient (or carrier) suchas sodium citrate or dicalcium phosphate or (a) fillers or extenders, asfor example, starches, lactose, sucrose, mannitol, and silicic acid; (b)binders, as for example, carboxymethylcellulose, alginates, gelatin,polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as forexample, glycerol; (d) disintegrating agents, as for example, agar-agar,calcium carbonate, potato or tapioca starch, alginic acid, certaincomplex silicates, and sodium carbonate; (a) solution retarders, as forexample, paraffin; (f) absorption accelerators, as for example,quaternary ammonium compounds; wetting agents, as for example, cetylalcohol and glycerol monostearate; (h) adsorbents, as for example,kaolin and bentonite; and (i) lubricants, as for example, talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, or mixtures thereof. In the case of capsules, and tablets, thedosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be used as fillers in softand hard filled gelatin capsules using such excipients as lactose ormilk sugar, as well as high molecular weight polyethylene glycols, andthe like.

Solid dosage forms such as tablets, dragées, capsules, pills, andgranules can be prepared with coatings and shells, such as entericcoatings and others well known in the art. They may also containopacifying agents and can also be of such composition that they releasethe active compound or compounds in a certain part of the intestinaltract in a delayed manner. Examples of embedding compositions that canbe used are polymeric substances and waxes. The active compounds canalso be in micro-encapsulated form, if appropriate, with one or more ofthe above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the active compounds, the liquid dosage form may containinert diluents commonly used in the art, such as water or othersolvents, solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethylformamide, oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil, and sesame seed oil, glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants,such as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents. Suspensions, in addition to the activecompound, may contain suspending agents, as for example, ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,microcrystalline cellulose, aluminum metahydroxide, bentonite,agar-agar, and tragacanth, or mixtures of these substances, and thelike.

Compositions for rectal administration are preferably suppositories,which can be prepared by mixing the compounds of the present inventionwith suitable non-irritating excipients or carriers such as cocoabutter, polyethylene glycol or a suppository wax, which are solid atordinary room temperature, but liquid at body temperature, andtherefore, melt in the rectum or vaginal cavity and release the activecomponent.

Dosage forms for topical administration of a compound of the presentinvention include ointments, powders, sprays and inhalants. The activecompound or fit compounds are admixed under sterile condition with aphysiologically acceptable carrier, and any preservatives, buffers, orpropellants that may be required. Ophthalmic formulations, eyeointments, powders, and solutions are also contemplated as being withinthe scope of this invention.

The compounds of the present invention can be administered to a patientat therapeutically effective dosage levels. The specific dosage anddosage range that can be used depends on a number of factors, includingthe requirements of the patient, the severity of the condition ordisease being treated, and the pharmacological activity of the compoundbeing administered.

The compounds of the present invention can be administered aspharmaceutically acceptable salts, co-crystals, esters, amides orprodrugs. The term “salts” refers to inorganic and organic salts ofcompounds of the present invention. The salts can be prepared in situduring the final isolation and purification of a compound, or byseparately reacting a purified compound in its free base or acid formwith a suitable organic or inorganic base or acid and isolating the saltthus formed. Representative salts include the hydrobromide,hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate,palmitiate, stearate, laurate, borate, benzoate, lactate, phosphate,tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate,mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, andthe like. The salts may include cations based on the alkali and alkalineearth metals, such as sodium, lithium, potassium, calcium, magnesium,and the like, as well as non-toxic ammonium, quaternary ammonium, andamine cations including, but not limited to, ammonium,tetramethylammonium, tetraethylammonium, me thylamine, dimethylamine,trimethylamine, triethylamine, ethylamine, and the like. See, forexample, S. M. Berge, et al., “Pharmaceutical Salts,” J Pharm Sci, 66:1-19 (1977).

Examples of pharmaceutically acceptable esters of the compounds of thepresent invention include C₁-C₈ alkyl esters. Acceptable esters alsoinclude C₅-C₇ cycloalkyl esters, as well as arylalkyl esters such asbenzyl. C₁-C₄ alkyl esters are commonly used. Esters of compounds of thepresent invention may be prepared according to methods that are wellknown in the art.

Examples of pharmaceutically acceptable amides of the compounds of thepresent invention include amides derived from ammonia, primary C₁-C₈alkyl amines, and secondary C₁-C₈ dialkyl amines. In the case ofsecondary amines, the amine may also be in the form of a 5 or 6 memberedheterocycloalkyl group containing at least one nitrogen atom. Amidesderived from ammonia, C₁-C₃ primary alkyl amines and C₁-C₂ dialkylsecondary amines are commonly used. Amides of the compounds of thepresent invention may be prepared according to methods well known tothose skilled in the art.

The term “prodrug” means compounds that are transformed in vivo to yielda compound of the present invention. The transformation may occur byvarious mechanisms, such as through hydrolysis in blood. A discussion ofthe use of prodrugs is provided by T. Higuchi and W. Stella, “Pro-drugsas Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, andin Bioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987.

To illustrate, if the compound of the invention contains a carboxylicacid functional group, a prodrug can comprise an ester formed by thereplacement of the hydrogen atom of the acid group with a group such as(C₁-C₈ alkyl, (C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl havingfrom 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having from 5 to10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbonatoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)aminomethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂₋₃)alkyl.

Similarly, if a compound of the present invention comprises an alcoholfunctional group, a prodrug can be formed by the replacement of thehydrogen atom of the alcohol group with a group such as(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanoyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, —P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate).

In addition, if a compound of the present invention comprises asulfonamide moiety, a prodrug can be formed by replacement of thesulfonamide N(H) with a group such as —CH₂P(O)(O(C₁-C₆)alkyl)₂ or—CH₂OC(O)(C₁-C₆)alkyl.

The compounds of the present invention also include tautomeric forms ofprodrugs.

The compounds of the present invention may contain asymmetric or chiralcenters, and therefore, exist in different stereoisomeric forms. It iscontemplated that all stereoisomeric forms of the compounds as well asmixtures thereof, including racemic mixtures, form part of the presentinvention. In addition, the present invention contemplates all geometricand positional isomers. For example, if the compound contains a doublebond or disubstituted cycloalkyl group, both the cis and trans isomers,unless the specific isomer is specified, as well as mixtures, arecontemplated. In disubstituted cycloalkyl containing compounds, the cisand trans isomers refer to the relative positions of the substitutions.For example:

(A) represents trans cyclobutyl isomer because the —CF₃ group ispointing up while the —CH₃ group is pointing down, while (B) representscis cyclobutyl isomer because both the —CF₃ group and the —CH₃ groupsare pointing down.

Mixtures of stereoisomers, such as diastereomeric mixtures, can beseparated into their individual stereochemical components on the basisof their physical chemical differences by known methods such aschromatography and/or fractional crystallization. Enantiomers can alsobe separated by converting the enantiomeric mixture into a diasteromericmixture by reaction with an appropriate optically active compound (e.g.,an alcohol), separating the diastereomers and converting (e.g.,hydrolyzing) the individual diastereomers to the corresponding pureenantiomers.

The compounds of general Formula (I) may also exist in the form ofatropisomers. Atropisomers are compounds with identical structuralformulae, but which have a particular spatial configuration resultingfrom a restricted rotation around a single bond, due to steric hindranceon either side of this single bond. Atropisomerism is independent of thepresence of stereogenic elements, such as an asymmetric carbon. Theterms “P atropisomer” or “M atropisomer” are used herein in order to beable to clearly name two atropisomers of the same pair. For example, thefollowing intermediate compound having the structure below can beseparated into the pair of atropisomers P and M via a chiral columnchromatography:

The compounds of the present invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater (hydrate), ethanol, and the like. The present inventioncontemplates and encompasses both the solvated and unsolvated forms.

It is also possible that compounds of the present invention may exist indifferent tautomeric forms. All tautomers of compounds of the presentinvention are contemplated. For example, all of the tautomeric forms ofthe tetrazole moiety are included in this invention. Also, for example,all keto-enol or imine-enamine forms of the compounds are included inthis invention. Other examples of tautomerism are as follows:

Those skilled in the art will recognize that the compound names andstructures contained herein may be based on a particular tautomer of acompound. While the name or structure for only a particular tautomer maybe used, it is intended that all tautomers are encompassed by thepresent invention, unless stated otherwise.

It is also intended that the present invention encompass compounds thatare synthesized in vitro using laboratory techniques, such as those wellknown to synthetic chemists; or synthesized using in vivo techniques,such as through metabolism, fermentation, digestion, and the like. It isalso contemplated that the compounds of the present invention may besynthesized using a combination of in vitro and in vivo techniques.

The present invention also includes isotopically labelled compounds,which are identical to those recited herein, but for the fact that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁶O,¹⁷O, ³¹F, ³²F, ³⁵S, ¹⁸F, and ³⁶Cl. In another aspect, the compounds ofthe present invention contain one or more deuterium atoms (2H) in placeof one or more hydrogen atoms.

Compounds of the present invention that contain the aforementionedisotopes and/or other isotopes of other atoms are within the scope ofthis invention. Certain isotopically labelled compounds of the presentinvention, for example those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetection. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labelled compounds of this inventioncan generally be prepared by substituting a readily availableisotopically labelled reagent for a non-isotopically labelled reagent.

The compounds of the present invention may exist in various solid statesincluding crystalline states and as an amorphous state. The differentcrystalline states, also called polymorphs, and the amorphous states ofthe present compounds are contemplated as part of this invention.

All patents and other publications recited herein are herebyincorporated by reference in their entirety.

The examples presented below illustrate specific embodiments of thepresent invention. These examples are meant to be representative and arenot intended to limit the scope of the claims in any manner.

It is noted that when a percent (%) is used with regard to a liquid, itis a percent by volume with respect to the solution. When used with asolid, it is the percent with regard to the solid composition. Materialsobtained from commercial suppliers were typically used without furtherpurification. Reactions involving air or moisture sensitive reagentswere typically performed under a nitrogen or argon atmosphere. Puritywas measured using high performance liquid chromatography (HPLC) systemwith UV detection at 254 nm and 215 nm (System A: HALO C8, 3.0×50 mm,2.7 am, 5 to 95% CH₃CN in H₂O with 0.1% TFA for 2.0 min at 2.0 mL/min)(Agilent Technologies, Santa Clara, Calif.). Silica gel chromatographywas generally performed with prepacked silica gel cartridges (BIOTAGE®,Uppsala, Sweden or Teledyne-Isco, Lincoln, Nebr.). ¹H NMR spectra wererecorded on a Bruker AV-400 (400 MHz) spectrometer (Bruker Corporation,Madison, Wis.) or a Varian (Agilent Technologies, Santa Clara, Calif.)400 MHz spectrometer at ambient temperature. All observed protons arereported as parts per million (ppm) downfield from tetramethylsilane(TMS) or other internal reference in the appropriate solvent indicated.Data are reported as follows: chemical shift, multiplicity (s=singlet,d=doublet, t=triplet, q=quartet, br=broad, m=multiplet), couplingconstants, and number of protons. Low-resolution mass spectral (MS) datawere determined on an Agilent 1100 Series (Agilent Technologies, SantaClara, Calif.) LC/MS with UV detection at 254 nm and 215 nm and a lowresonance electrospray mode (ESI).

The following abbreviations may be used herein:

-   2-PrOH Isopropanol-   AgOTf silver(I) trifluoromethanesulfonate-   AIBN Azobisisobutyronitrile-   aq. Aqueous-   Bu Butyl-   ca. Circa-   Cm centimeter(s)-   CPhos 2-dicyclohexylphosphino-2′,6′-dimethylamino-1,1′biphenyl-   DAST diethylaminosulfur trifluoride-   Dba Dibenzylideneacetone-   DCM Dichloromethane-   Deoxy-Fluor bis(2-methoxyethyl)aminosulfurtrifluoride-   DIPEA N,N-diisopropylethylamine-   DMF N,N-dimethylformamide-   DMSO Dimethylsulfoxide-   ESI or ES electrospray ionization-   Et Ethyl-   Et₂O diethyl ether-   EtOAc ethyl acetate-   EtOH Ethanol-   G gram(s)-   H hour(s)-   HPLC high pressure liquid chromatography-   IPA 2-propanol-   Kg kilogram(s)-   L liter(s)-   LCMS liquid chromatography mass spectroscopy-   LHMDS lithium hexamethyldisilazide-   M Molar-   m/z mass divided by charge-   Me Methyl-   Me OH Methanol-   Me-THF Methyl tetrahydrofuran-   Mg milligram(s)-   MHz Megahertz-   Min minute(s)-   mL or ml milliliter(s)-   Mmol millimole(s)-   Mol mole(s)-   MTBE methyl tert-butyl ether-   N Normal-   NaOMe sodium methoxide-   n-Bu n-butyl-   NEt₃ Triethylamine-   NMR nuclear magnetic resonance-   OAc Acetate-   OTf Trifluoromethanesulfonate-   PFP-OH Perfluorophenol-   Ph Phenyl-   PhMe Toluene-   PMB 4-methoxy benzyl-   Ppm parts per million-   Pr Propyl-   rac racemic-   rt room temperature-   sat. Saturated-   SFC supercritical fluid chromatography-   TBAF tetra-n-butylammonium fluoride-   TFA trifluoroacetic acid-   THF Tetrahydrofuran-   Ti(OiPr)₄ titanium(IV) isopropoxide-   TLC thin-layer chromatography-   TMS-CF₃ (trifluoromethyl)trimethylsilane-   wt % percentage by weight-   XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene-   XtalFluor-M difluoro(morpholino)sulfonium tetrafluoroborate

The following compounds presented herein, as examples of the presentinvention, and intermediates thereof as building blocks to preparecompounds provided by the invention, may be made by the various methodsand synthetic strategies taught herein below. These compounds, andothers provided by the invention, may also be prepared using methodsdescribed in International Publication No. WO2014/201206, filed Jun. 12,2014, which specification is incorporated herein by reference in theirentirety.

In addition, the present inventors have developed a photochemicalatrop-selective ring-closure to form N-aryl quinolinones compounds.Specifically, the P atropisomer compound 3 is selectively formed in thephotochemical reaction of the invention. A general representation of thephotochemistry step of the present invention is described below:

The reaction relies on UV or near-UV light to excite the olefin 1;wherein R is halo; and R¹ is C₁-C₆alkyl; and induce a cis-transisomerization to transiently form 2; wherein R is halo; and R¹ isC₁-C₆alkyl. Preferably, R¹ is ethyl. Cis olefin 2 can then be activatedby chiral acid (S)-TRIP to asymmetrically form ring-closed quinolinone3, wherein R is as defined above. Preferably, R is Br. A screen ofchiral phosphoric acids revealed that (S)-TRIP was the preferred chiralacid. The preferred organic solvent is dichloromethane. Thephotochemical reaction has been scaled to 1 g in a batch reactor and hasalso been demonstrated in a small photochemical flow reactor.

The present photochemical step can operate well without the present of abulky barrier substituent to rotation, such as tert-butyl group in thestarting material. Rather, the present novel photochemical step has beendemonstrated in the presence of a much smaller methoxy group in thestarting material. The mild reaction conditions further allow forcompounds with low barriers to rotation to be prepared in astereoselective fashion.

Intermediate A:(P)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

Step 1: 4-Bromo-2-Iodoaniline

To a solution of 4-bromo-aniline (500 g, 2.90 mol) in cyclohexane (2.5L) was added iodine (368 g, 1.45 mol), and the mixture was heated at 50°C. After 30 min, the reaction mixture became homogenous, and 30% aqueoushydrogen peroxide solution (250 mL) was added to the reaction mixture.The reaction was heated for 4 h at 50° C. The reaction was cooled toroom temperature, diluted with ethyl acetate (5.0 L) and washed withaqueous sodium sulphite (2.5 kg in 4.0 L) solution. The organic layerwas washed with water (3.0 L) and brine (3.0 L), dried over magnesiumsulfate, filtered and concentrated under reduced pressure to obtain theinitial product which was purified by column chromatography (silica gel;mesh size 60-120, elution 0-20% ethyl acetate and hexanes) to get4-bromo-2-iodoaniline (650 g, 75%), as an off white solid. TLC solventsystem: 100% hexanes. Product's R_(f): 0.6. MS (ESI, positive ion) m/z:297.0 (M+1). ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J=2.5 Hz, 1H), 7.23 (dd,J=8.4, 2.1 Hz, 1H), 6.62 (d, J=8.3 Hz, 1H), 4.09 (s, 2H).

Step 2: Ethyl (E)-3-(2-Amino-5-Bromophenyl)Acrylate

To a solution of 4-bromo-2-iodoaniline (750 g, 2.51 mol) in DMF (5.0 L)was added ethyl acrylate (277 g, 2.76 mol) and sodium bicarbonate (680g, 6.29 mol). The reaction mixture was degassed with nitrogen for 20 minfollowed by the addition of palladium acetate (28.8 g, 128.27 mmol). Thereaction mixture was heated at 70° C. for 3 h. The reaction was filteredthrough CELITE® and the CELITE bed was washed with ethyl acetate (2×500mL). The filtrate was concentrated under reduced pressure to obtain aresidue which was purified by column chromatography (silica gel; meshsize 60-120, elution 0-20% ethyl acetate in hexanes) to obtain (E)-ethyl3-(2-amino-5-bromophenyl)acrylate (620 g, 77%), as yellow solid. TLCsolvent system: 20% ethyl acetate in hexanes. Product's R_(f): 0.4. MS(ESI, positive ion) m/z; 270.2 (M+1). ¹H NMR (400 MHz, DMSO) δ 7.75 (d,J=16.1 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.16 (dd, J=9.1, 2.4 Hz, 1H),6.66 (d, J=8.6 Hz, 1H), 6.43 (d, J=8.6 Hz, 1H), 5.81 (s, 2H), 4.20 (q,J=7.2 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H). Other acrylates can be used inplace of ethyl acrylate to provide different esters. For example methylacrylate, propyl acrylate, butyl acrylate, and others may be usedinstead of ethyl acrylate.

Step 3: Ethyl (E)-3-(2-Amino-5-(Benzylthio)Phenyl) Acrylate

To a solution of (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate (620 g,2.29 mol) in 1,4-dioxane (4.0 L) was added DIPEA (1.26 L, 8.88 mol, 3.9equiv, GLR), and the mixture was degassed with nitrogen for 20 mins.XantPhos (92.9 g, 106 mmol), andtris(dibenzylideneacetone)dipalladium(0) (84 g, 91.0 mmol) were added tothe reaction mixture. The mixture was purged with nitrogen and heated to80° C. for 30 min. The reaction was cooled to RT, benzyl mercaptan(455.5 g, 3.67 mol) was added, and the reaction was heated at 80° C. foran additional 4 h. The reaction was cooled to room temperature anddiluted with ethyl acetate (4.0 L). The mixture was filtered throughCELITE and the CELITE bed was washed with ethyl acetate (2×1.0 L). Thefiltrate was concentrated under reduced pressure to obtain the initialproduct which was purified by chromatography (silica gel; mesh size60-120, elution 0-40% ethyl acetate and petroleum ether) to obtain(E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (520 g, 72.0%), asyellow solid. TLC solvent system: 30% ethyl acetate in hexanes.Product's R_(f): 0.4. MS (ESI, positive ion) m/z; 314.1 (M+1). ¹H NMR(400 MHz, DMSO) δ 7.79 (d, J=16.1 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H),7.25-7.17 (m, 5H) 7.10 (dd, J=8.4, 2.1 Hz, 1H), 6.61 (d, J=8.3 Hz, 1H),6.32 (d, J=15.2 Hz, 1H), 5.75 (s, 2H), 4.20 (q, J=7.2 Hz, 2H), 4.01 (s,2H), 1.27 (t, J=7.2 Hz, 3H).

Step 4: 1-Bromo-2-Fluoro-4-Iodo-S-Methoxybenzene

To a solution of 2-bromo-1-fluoro-4-methoxybenzene (500.0 g, 2.44 mol)in DCM (5.0 L) was added silver trifluoromethanesulfonate (686.0 g, 2.68mol) and the reaction mixture was stirred for 20 min. Iodine (678.0 g,2.68 mol) was added to the reaction and the mixture was stirred at roomtemperature for 16 h. The mixture was diluted with DCM (3.0 L) andfiltered through CELITE. The CELITE bed was washed with DCM (2×1.0 L)and the filtrate was washed with 20% aqueous sodium thiosulfate (3.0 L)and saturated aqueous sodium bicarbonate solution (3.0 L). The organiclayer was dried over sodium sulfate, filtered and concentrated underreduced pressure to obtain the initial product which was purified bychromatography (silica gel; mesh size 60-120, elution 0-5% ethyl acetateand petroleum ether) to get 1-bromo-2-fluoro-4-iodo-5-methoxybenzene(720 g, 87%), as off-white solid. TLC solvent system: 100% hexanes.Product's R_(f): 0.6. MS (ESI, positive ion) m/z: 331.0 (M+1). ¹H NMR(400 MHz, CDCl₃) δ 7.55 (d, J=7.2 Hz, 1H), 6.95 (d, J=5.6 Hz, 1H), 3.89(s, 3H).

Step 5: Ethyl(E)-3-(5-(Benzylthio)-2-((4-Bromo-5-Fluoro-2-Methoxyphenyl)Amino)Phenyl)Acrylate

To a solution of (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (300g, 958.1 mmol) and 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (348.0 g,1051.6 mmol) in toluene (2.5 L) was added Cs₂CO₃ (468 g, 1436.3 mmol).The resulting mixture was degassed with nitrogen for 20 mins. Pd₂(dba)₃(35 g, 38.2 mmol) and XantPhos (44.6 g, 76.4 mmol) were added to thereaction mixture and the mixture was heated at 110° C. for 5 h. Thereaction mixture was allowed to cool to room temperature, diluted withdichloromethane (2.0 L) and filtered through CELITE. The filtrate wasconcentrated under reduced pressure to obtain the initial product whichwas purified by stirring with 5% ethyl acetate in hexanes (3.0 L) for 30min and filtered to obtain (E)-ethyl3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate(350 g, 71%) as yellow solid. TLC solvent system: 30% ethyl acetate inhexanes. Product's R_(f): 0.5. MS (ESI, positive ion) m/z; 516.2 (M+1).¹H NMR (400 MHz, DMSO) δ 7.73-7.61 (m, 3H), 7.34-7.15 (m, 6H), 7.02 (d,J=11.4 Hz, 1H), 6.60 (d, J=21.2 Hz, 1H), 6.33 (d, J=14.1 Hz, 1H), 4.26(s, 2H), 4.16-4.09 (m, 2H), 3.81 (s, 3H), 1.22 (t, J=7.2 Hz, 3H). Note:NH proton not observed.

Step 6:6-(Benzylthio)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)Quinolin-2(1H)-One

To a solution of (E)-ethyl3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate(250.0 g, 484.0 mmol) in methanol (2.5 L) was addedtri(n-butyl)phosphine (50% solution in ethyl acetate, 48.9 mL, 96.8mmol) and the reaction mixture was heated at 70° C. for 5 h. Thereaction mixture was allowed to cool to rt, and was then concentratedunder reduced pressure to obtain the initial product which was purifiedby stirring with 5% ethyl acetate in hexanes (1.0 mL) and filtered toobtain6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one(201.0 g, 88%) as an off white solid. TLC solvent system: 30% ethylacetate in hexanes. Product's R_(f): 0.3. MS (ESI, positive ion) m/z;470.0 (M+1). ¹H NMR (400 MHz, DMSO) δ 7.92 (d, J=9.1 Hz, 1H), 7.79 (d,J=1.7 Hz, 1H), 7.65 (d, J=6.1 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.40-7.22(m, 6H), 6.68 (d, J=9.6 Hz, 1H), 6.56 (d, J=8.8 Hz, 1H), 4.24 (s, 2H),3.69 (s, 3H).

Alternatively, the P atropisomer title compound of step 6 can beselectively prepared by using a photochemistry route from ethyl(E)-3-[5-benzylsulfanyl-2-(4-bromo-5-fluoro-2-methoxy-anilino)phenyl]prop-2-enoatestarting material as described in the following procedures:

Photochemistry Preparation Method 1

To a flask was added (E)-ethyl3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenypacrylate(4.0 g, 7.6 mmol),(S)-3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diylhydrogen phosphate ((S)-TRIP) (290 mg, 0.38 mmol) and DCM (40 mL). Theresulting solution was continuously stirred and recirculated for 2.5 hthrough narrow-diameter tubing that was exposed to 467 nm LED light. Thereaction solution was concentrated to approximately 8 mL and chargedwith MeOH (80 mL). The solution was concentrated to approximately 50 mLand heated to 60° C. The solution was filtered to remove any precipitateand then allowed to cool to room temperature overnight. The resultingslurry was cooled to 0° C. for 2 h and then filtered. The filter cakewas rinsed with cold MeOH to deliver(P)-6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-oneas a tan solid (2.12 g, 89 wt %, 4.0 mmol). ^(1H) NMR (300 MHz, DMSO-d6)δ 7.95 (d, J=9.6 Hz, 1H), 7.79 (d, J=2.2 Hz, 1H), 7.64 (d, J=6.3 Hz,1H), 7.55 (d, J=8.7 Hz, 1H), 7.42-7.16 (m, 6H), 6.67 (d, J=9.5 Hz, 1H),6.55 (d, J=8.8 Hz, 1H), 4.24 (s, 2H), 3.68 (s, 3H). ¹⁹F NMR (282 MHz,DMSO-d6) δ −117.08 (dd, 1F, J=8.7, 6.3 Hz). ee determined by chiralnormal phase chromatography (CHIRALPAK IC-3, 4.6×150×3), mobile phase of60% Heptane/40% (0.2% ethanesulfonic acid in Ethanol) v/v, with flowrate of 1.5 mL/min.

Photochemistry Preparation Method 2

To a flask was added (E)-ethyl3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenypacrylate(50.0 g, 96.8 mmol),(S)-3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diylhydrogen phosphate ((S)-TRIP) (1.46 g, 1.94 mmol), toluene (750 mL) andDCM (750 mL). The reaction headspace was purged with N₂. The reactionsolution was warmed to 30° C. and stirred. The solution was recirculatedat a flow rate of 50 g/min via peristaltic pump for 10 h through ⅛″ FEPtubing (approximately 10 mL internal volume) that was exposed to 457 nmLED light. The reaction solution was concentrated to a yellow-brownsolid and then slurried in ^(i)PrOAc (250 mL) for 30 min at 30° C. Tothe slurry was added heptane (500 mL) over 30 min. The slurry was cooledto 0° C. over 2 h and then placed in a −20° C. freezer for 36 h. Theslurry was filtered and the filter cake was rinsed with 10% v/v^(i)PrOAc/heptane (2×150 mL). The solids were dried in a vacuum oven toprovide(P)-6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-oneas a tan solid (34.7 g, 98 wt %, 72.6 mmol, 89% ee).

Steps 7 & 8: Perfluorophenyl1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-2-Oxo-1,2-DihydroQuinoline-6-Sulfonate

To a solution of6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one(250.0 g, 531.5 mmol) in acetonitrile (2.5 L) were added acetic acid(200 mL) and water (130 mL). The resulting mixture was cooled to 0° C.and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (188.5 g, 956.7mmol) was added portion-wise over 20 min keeping the internaltemperature below 5° C. The resulting suspension was stirred at 0-5° C.under nitrogen for 45 min. Then a solution of pentafluorophenol (127.2g, 690.95 mmol) in acetonitrile (200 mL) was added over 5 min followedby NEt₃ (307.7 mL, 2.12 mol) over 20 min keeping the internaltemperature below 5° C. The mixture was continued to be stirred at 0-5°C. for 30 min. Water (4.0 L) was added and extracted with ethyl acetate(2×2.0 L). The organic layer was washed with brine (1.0 L), dried oversodium sulfate, filtered and concentrated under reduced pressure toobtain the initial product which was purified by stirring with isopropylalcohol:hexanes (1:1, 1.0 L) and filtered to obtain perfluorophenyl1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(190 g, 60%) as white solid. TLC solvent system: 30% ethyl acetate inpet ether, Product's R_(f): 0.4. MS (ESI, positive ion) m/z; 594.2(M+1). ¹H-NMR (400 MHz, DMSO) δ ppm 8.60 (d, J=2.0 Hz, 1H), 8.26 (d,J=9.8 Hz, 1H), 7.95 (dd, J=2.2, 9.1 Hz, 1H), 7.70 (t, J=8.6 Hz, 2H),6.95-6.88 (m, 2H), 3.72 (s, 3H).

Step 9: (P)-Perfluorophenyl1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonate

Racemic perfluorophenyl1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(76.90 g) was separated via Chiralcel OJ column (40% MeOH/60% CO₂) togive (P)-perfluorophenyl1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonateand (M)-perfluorophenyl1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonateas pale yellow flocculent solids. Data for peak 1: m/z (ESI) 594.0(M+H)⁺. Data for peak 2: m/z (ESI) 594.0 (M+H)⁺.

Step 10:(P)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A THF (200 mL) solution of (P)-perfluorophenyl1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(6.00 g, 10.10 mmol) and 3-aminoisoxazole (0.821 mL, 11.11 mmol) in a250-mL round-bottom flask was cooled to 0° C., and lithiumbis(trimethylsilyl)amide, (1.0 M solution in THF, 21.20 mL, 21.20 mmol)was added dropwise. After stirring the yellow solution at 0° C. for 15min, it was quenched at 0° C. with 1 N HCl and extracted thrice withEtOAc. The organic extracts were combined, dried over MgSO₄, filtered,and concentrated to a light tan residue. Et₂O was added, and the slurrywas triturated and sonicated. Filtration afforded an off-white solid,which was washed twice with Et₂O and dried in vacuo to afford 3.88 g ofproduct as an off-white solid. The filtrate was concentrated in vacuoand purified via column chromatography (12 g silica gel, 35% to 100%EtOAc/hept gradient) to afford an additional 1.36 g of product as a paleyellow flocculent solid. A total of 5.24 g of(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamidewas afforded. m/z (ESI) 494.1 (M+H)⁺.

Intermediate A: (3-(Tert-Butyl)Cyclobutyl)Zinc(II) Iodide, 0.2 M in THF

A three-necked oven-dried round-bottom flask equipped with a magneticstir bar and a rubber septum was charged with lithium chloride (96 mg,2.3 mmol). The vessel was heated with a heat gun for 10 min under vacuumand backfilled with nitrogen after cooling to room temperature. Zinc(148 mg, 2.27 mmol) was added. The vessel was again heated with a heatgun for 10 min under vacuum and backfilled with nitrogen after coolingto room temperature. THF (3.4 mL) and 1,2-dibromoethane (4.9 μL, 0.057mmol) were added via syringe and the reaction mixture was heated at 60°C. until bubbling occurred. After cooling to room temperature,chlorotrimethylsilane (4.4 μL, 0.034 mmol) and a solution of iodine (2.9mg, 0.011 mmol) in THF (0.1 mL) were added via syringe. The reactionmixture was heated at 60° C. for 20 min and then cooled to roomtemperature. 1-(tert-Butyl)-3-iodocyclobutane (270 mg, 1.13 mmol) wasadded, and the reaction was stirred at 50° C. for 18 h. The reactionmixture was allowed to stand at room temperature for 1 h. The solutionwas titrated by adding dropwise to a cooled (0° C.) solution of iodine(3 mg, 0.012 mmol) in lithium chloride (0.5 M in THF, 2.3 mL, 1.1 mmol)until the orange color disappeared. 0.06 mL of solution was used,corresponding to a concentration of 0.2 M.

Intermediate B: 5,8-Dioxaspiro[3.4]Octan-2-Ylzinc(II) Bromide, 0.1 MinTHF

An oven-dried round-bottom flask equipped with a magnetic stir bar and arubber septum was charged with lithium chloride (0.878 g, 20.72 mmol).The vessel was heated with a heat gun for 10 min under vacuum andbackfilled with nitrogen after cooling to room temperature. Zinc (1.355g, 20.72 mmol) was added. The vessel was again heated with a heat gunfor 10 min under vacuum and backfilled with nitrogen after cooling toroom temperature. THF (13.8 mL) and 1,2-dibromoethane (0.045 mL, 0.518mmol) were added via syringe and the reaction mixture was heated at 60°C. until bubbling occurred. After cooling to room temperature,chlorotrimethylsilane (0.040 mL, 0.311 mmol) and a solution of iodine(0.026 g, 0.104 mmol) in THF (0.2 mL) were added via syringe. Thereaction mixture was heated at 60° C. for 20 min and then cooled to roomtemperature. 2-Bromo-5,8-dioxaspiro[3.4]octane (1.3 mL, 10 mmol) wasadded and the reaction was stirred at 50° C. for 16 h. The resultingsolution was used as is.

Intermediate C: (3-(Trifluoromethyl)Cyclobutyl) Zinc(II) Bromide, 0.15 Min THF

This intermediate was synthesized in the same manner and stoichiometryas Intermediate B using 1-bromo-3-(trifluoromethyl)cyclobutane (2.00 g,9.85 mmol).

Intermediate D: Perfluorophenyl(P)-1-(4-Bromo-2-Methoxyphenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonate

Step 1: (E)-Ethyl3-(5-(Benzylthio)-2-((4-Bromo-2-Methoxyphenyl)Amino)Phenyl)Acrylate

A round-bottom flask was charged with (E)-ethyl3-(2-amino-5-(benzylthio)phenyl)acrylate (2.39 g, 7.63 mmol),4-bromo-1-iodo-2-methoxybenzene (2.86 g, 9.15 mmol), XantPhos (0.221 g,0.381 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.175 g, 0.191mmol), and cesium carbonate (4.97 g, 15.25 mmol) were added. A refluxcondenser was attached and the flask was lowered into a 110° C. heatingbath. After 2 h, an additional portion of cesium carbonate (1.4 g) wasadded, and the bath temperature was raised to 120° C. The mixture washeated for another 2 h then cooled to room temperature, diluted withEtOAc, and filtered through CELITE with the aid of EtOAc. The filtratewas concentrated. The oily residue was taken up in 2-PrOH. The mixturewas concentrated to give a yellow solid with some oily solid present.The mixture was taken up in 2-PrOH to give a suspension, and thesuspension was stirred for 16 h. The mixture was filtered, and thefiltered solid was washed with 2-PrOH (3×). The collected solid wasdried on the filter under a flow of N₂ for 15 min to give (E)-ethyl3-(5-(benzylthio)-2-((4-bromo-2-methoxyphenyl)amino)phenyl) acrylate(3.136 g, 6.29 mmol, 83% yield) as a bright-yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.72 (d, J=16.0 Hz, 1H), 7.68 (d, J=2.2 Hz, 1H),7.47 (s, 1H), 7.37-7.19 (m, 6H), 7.13 (d, J=2.2 Hz, 1H), 6.94 (dd,J=2.2, 8.4 Hz, 1H), 6.86 (d, J=8.5 Hz, 1H), 6.55 (s, 1H), 6.52 (d, J=7.7Hz, 1H), 4.24 (s, 2H), 4.15 (q, J=7.1 Hz, 2H), 3.82 (s, 3H), 1.23 (t,J=7.1 Hz, 3H). m/z (ESI) 498.0 (M+H)⁺.

Step 2: 6-(Benzylthio)-1-(4-Bromo-2-Methoxyphenyl)Quinolin-2(1H)-One

A round-bottom flask was charged with (E)-ethyl3-(5-(benzylthio)-2-((4-bromo-2-methoxyphenyl)amino)phenypacrylate (3.13g, 6.28 mmol) and MeOH (31.4 mL) to give a yellow suspension. Sodiummethoxide (25 wt % in MeOH, 0.271 mL, 1.256 mmol) was added. A refluxcondenser was attached, and the flask was lowered into a 75° C. heatingbath. The bath quickly spiked to ca. 80-85° C., but returned to 70-75°C. after 30 min. The reaction was stirred for 16 h, and the mixture wasdiluted with DCM and concentrated. The residue was purified bychromatography on silica gel (50-g SNAP Ultra column, 25-g silica gelloading column, 10-60% EtOAc/Heptane) to give6-(benzylthio)-1-(4-bromo-2-methoxyphenyl)quinolin-2(1H)-one (1.95 g,4.31 mmol, 69% yield) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm7.94 (d, J=9.5 Hz, 1H), 7.78 (d, J=2.2 Hz, 1H), 7.50 (d, J=2.1 Hz, 1H),7.43-7.16 (m, 8H), 6.66 (d, J=9.6 Hz, 1H), 6.47 (d, J=8.8 Hz, 1H), 4.23(s, 2H), 3.69 (s, 3H). m/z (ESI) 452.0 (M+H)⁺.

Step 3: Perfluorophenyl1-(4-Bromo-2-Methoxyphenyl)-2-Oxo-1,2-DIHYDROQUINOLINE-6-SULFONATE

A round-bottom flask was charged with6-(benzylthio)-1-(4-bromo-2-methoxyphenyl)quinolin-2(1H)-one (1.777 g,3.93 mmol), acetonitrile (18.49 mL), acetic acid (0.693 mL), and water(0.462 mL) to give a solution. The flask was cooled in an ice-water bathfor 10 min, then 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.813g, 4.12 mmol) was added in one portion. After 20 min, an additionalportion of 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.813 g,4.12 mmol) was added in one portion. After another 20 min,2,3,4,5,6-pentafluorophenol (1.085 g, 5.89 mmol) was added, and themixture was stirred for 5 min. Triethylamine (2.190 mL, 15.71 mmol) wasadded dropwise over 30 s then the mixture was stirred for 20 min. Thereaction mixture was diluted with water and extracted with DCM (3×). Thecombined organic extracts were dried over sodium sulfate, filtered, andconcentrated. The residue was purified by chromatography on silica gel(50-g SNAP Ultra column, 25-g silica gel loading column, 10-60%EtOAc/Heptane). Perfluorophenyl1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(1.644 g, 2.85 mmol, 72.6% yield) was isolated as a white foam. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 8.59 (d, J=2.2 Hz, 1H), 8.24 (d, J=9.6 Hz, 1H),7.95 (dd, J=2.3, 9.1 Hz, 1H), 7.56 (d, J=1.9 Hz, 1H), 7.44-7.26 (m, 2H),6.86 (dd, J=9.4, 13.7 Hz, 2H), 3.72 (s, 3H). m/z (ESI) 575.9 (M+H)⁺.

Step 4: Perfluorophenyl(P)-1-(4-Bromo-2-Methoxyphenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonateand Perfluorophenyl(M)-1-(4-Bromo-2-Methoxyphenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonate

Racemic perfluorophenyl1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (3000g) was separated in 5 600-g batches using a Regis Whelk-O (S,S), 3×15 cmcolumn. The mobile phase was run under isocratic conditions;supercritical CO₂ with 60% [2:3 isopropanol:dichloromethane]; flow rate:150 mL/min. The first eluting peak was assigned perfluorophenyl(P)-1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(1459.2 g). The second eluting peak was assigned perfluorophenyl(M)-1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(1492.9 g).

Step 5:(P)-1-(4-Bromo-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

Racemic1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(400 mg) was purified using a (S,S) Whelk-O, 2×15 cm column. The mobilephase was run under isocratic conditions; supercritical CO₂ with 60%isopropanol; flow rate: 80 mL/min. The first eluting peak was assigned(M)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(150 mg). The second eluting peak was assigned(P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(154 mg). Data for peak 1: ¹H NMR (400 MHz, ACETONITRILE-d₃) δ ppm8.65-8.94 (m, 1H), 8.37 (d, J=1.9 Hz, 1H), 8.23 (d, J=2.3 Hz, 1H), 7.97(d, J=9.3 Hz, 1H), 7.78 (dd, J=8.9, 2.3 Hz, 1H), 7.43 (d, J=2.1 Hz, 1H),7.34 (dd, J=8.3, 2.1 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 6.70-6.80 (m, 2H),6.45 (d, J=1.9 Hz, 1H), 3.69 (s, 3H). m/z (ESI, positive ion) 476.0(M+H)⁺. Data for peak 2: ¹H NMR (400 MHz, ACETONITRILE-d₃) 6 ppm8.72-8.87 (m, 1H), 8.37 (d, J=1.7 Hz, 1H), 8.23 (d, J=2.1 Hz, 1H), 7.97(d, J=9.5 Hz, 1H), 7.78 (dd, J=9.0, 2.2 Hz, 1H), 7.43 (d, J=2.1 Hz, 1H),7.34 (dd, J=8.3, 1.9 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 6.69-6.80 (m, 2H),6.45 (d, J=1.9 Hz, 1H), 3.69 (s, 3H). m/z (ESI, positive ion) 476.0(M+H)⁺.

Intermediate E: N-(4-Methoxybenzyl)Isoxazol-3-Amine

To a 20-L round-bottom flask was added isoxazol-3-amine (150 g, 1784mmol) and 4-methoxybenzaldehyde (274 g, 2016 mmol) in methanol (9000mL), water (150 mL), and acetic acid (101 mL) and stirred for 15 min atroom temperature. Then molybdenum dichloride dioxide (17.74 g, 89 mmol)and phenylsilane (193 g, 1784 mmol) were added. The reaction mixture wasstirred at room temperature for 16 h. After completion of the reaction,the reaction mass was concentrated, diluted with dichloromethane (5000mL) and washed with sat. aq. NaHCO₃ (2000 mL). The organic layer waswashed with water (2000 mL) and dried over Na₂SO₄. The solution wasfiltered and concentrated in vacuo to give the initial product as anorange solid. The initial product was absorbed onto a plug of silica geland purified by column chromatography (Silica gel, 60-120 mesh) elutingwith a gradient of 0% to 30% EtOAc in hexane, to provideN-(4-methoxybenzyl)isoxazol-3-amine (272 g, 1332 mmol, 75% yield) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.36 (d, J=1.8 Hz, 1H),7.16-7.37 (m, 2H), 6.71-6.97 (m, 2H), 6.56 (t, J=6.0 Hz, 1H), 5.97 (d,J=1.8 Hz, 1H), 4.18 (d, J=6.0 Hz, 2H), 3.73 (s, 3H). m/z (ESI, positiveion) 205.1 (M+H)⁺.

Intermediate F:(P)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

Step 1: 4-Bromo-2-Iodoaniline

To a solution of 4-bromo-aniline (500 g, 2.90 mol, 2.0 equiv, SaibainChem) in cyclohexane (2.5 L) was added iodine (368 g, 1.45 mol, 1.0equiv, Qualigens) and the mixture was heated at 50° C. After 30 min, thereaction mixture became homogenous. 30% aqueous hydrogen peroxidesolution (250 mL, Spectrochem) was added to the reaction mixture. Thereaction was heated for 4 h at 50° C. The reaction was cooled to roomtemperature, diluted with ethyl acetate (5.0 L) and washed with aqueoussodium-sulphite (2.5 Kg in 4.0 L) solution. The organic layer was washedwith water (3.0 L) and brine (3.0 L) dried over magnesium sulfate,filtered and concentrated under reduced pressure to obtain the initialproduct which was purified by column chromatography (silica gel; meshsize 60-120, elution 0-20% ethyl acetate and hexanes) to get4-bromo-2-iodoaniline (650 g, 75.0%), as off white solid. TLC solventsystem: 100% hexanes. Product's R_(f): 0.6. MS (ESI, positive ion) m/z:297.0 (M+1). ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d, J=2.5 Hz, 1H), 7.23 (dd,J=8.4, 2.1 Hz, 1H), 6.62 (d, J=8.3 Hz, 1H), 4.09 (s, 2H).

Step 2: Ethyl (E)-3-(2-Amino-5-Bromophenyl)Acrylate

To a solution of 4-bromo-2-iodoaniline (750 g, 2.51 mol, 1.0 equiv) inDMF (5.0 L) was added ethyl acrylate (277 g, 2.76 mol, 1.1 equiv, Avra)and sodium bicarbonate (680 g, 6.29 mol, 2.5 equiv). The reactionmixture was degassed with nitrogen for 20 min followed by the additionof palladium acetate (28.8 g, 128.27 mmol, 0.05 equiv, HindustanPlatinum). The reaction mixture was heated at 70° C. for 3h. Thereaction was filtered through CELITE® and the CELITE® bed was washedwith ethyl acetate (2×500 mL). The filtrate was concentrated underreduced pressure to obtain the initial product which was purified bycolumn chromatography (silica gel; mesh size 60-120, elution 0-20% ethylacetate in hexanes) to obtain (E)-ethyl3-(2-amino-5-bromophenyl)acrylate (620 g, 77.0%), as yellow solid. TLCsolvent system: 20% ethyl acetate in hexanes. Product's R_(f): 0.4. MS(ESI, positive ion) m/z; 270.2 (M+1). ¹H NMR (400 MHz, DMSO) δ 7.75 (d,J=16.1 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.16 (dd, J=9.1, 2.4 Hz, 1H),6.66 (d, J=8.6 Hz, 1H), 6.43 (d, J=8.6 Hz, 1H), 5.81 (s, 2H), 4.20 (q,J=7.2 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H).

Step 3: Ethyl (E)-3-(2-Amino-5-(Benzylthio)Phenyl)Acrylate

To a solution of (E)-ethyl 3-(2-amino-5-bromophenyl)acrylate (620 g,2.29 mol, 1.0 equiv) in 1,4-dioxane (4.0 L) was added DIPEA (1.26 L,8.88 mol, 3.9 equiv, GLR) and degassed with nitrogen for 20 mins.XantPhos (92.9 g, 106 mmol, 0.05 equiv, GLR), andtris(dibenzylideneacetone)dipalladium (84 g, 91.0 mmol, 0.04 equiv,Hindustan Platinum) was added to the reaction mixture. The mixture waspurged with nitrogen and heated to 80° C. for 30 mins. The reaction wascooled to RT and benzyl mercaptan (455.5 g, 3.67 mol, 1.6 equiv, AlfaAesar) was added and the reaction was heated at 80° C. for an additional4 h. The reaction was cooled to room temperature and diluted with ethylacetate (4.0 L). The mixture was filtered through CELITE® and theCELITE® bed was washed with ethyl acetate (2×1.0 L). The filtrate wasconcentrated under reduced pressure to obtain the initial product whichwas purified by chromatography (silica gel; mesh size 60-120, elution0-40% ethyl acetate and petroleum ether) to obtain (E)-ethyl3-(2-amino-5-(benzylthio)phenyl)acrylate (520 g, 72.0%), as yellowsolid. TLC solvent system: 30% ethyl acetate in hexanes. Product'sR_(f): 0.4. MS (ESI, positive ion) m/z; 314.1 (M+1). ¹H NMR (400 MHz,DMSO) δ 7.79 (d, J=16.1 Hz, 1H), 7.37 (d, J=2.0 Hz, 1H), 7.25-7.17 (m,5H) 7.10 (dd, J=8.4, 2.1 Hz, 1H), 6.61 (d, J=8.3 Hz, 1H), 6.32 (d,J=15.2 Hz, 1H), 5.75 (s, 2H), 4.20 (q, J=7.2 Hz, 2H), 4.01 (s, 2H), 1.27(t, J=7.2 Hz, 3H).

Step 4: 1-Bromo-2-Fluoro-4-Iodo-5-Methoxybenzene

To a solution of 2-bromo-1-fluoro-4-methoxybenzene (500.0 g, 2.44 mol,1.0 equiv) in DCM (5.0 L) was added silver trifluoromethane sulfonate(686.0 g, 2.68 mol, 1.1 equiv, Angene) and the reaction mixture wasstirred for 20 mins. Iodine (678.0 g, 2.68 mol, 1.1 equiv) was added tothe reaction and the mixture was stirred at room temperature for 16h.The mixture was diluted with DCM (3.0 L) and filtered through CELITE®.The CELITE bed was washed with DCM (2×1.0 L) and the filtrate was washedwith 20% aqueous sodium thiosulfate (3.0 L) and saturated aqueous sodiumbicarbonate solution (3.0 L). The organic layer was dried over sodiumsulfate, filtered and concentrated under reduced pressure to obtain theinitial product which was purified by chromatography (silica gel; meshsize 60-120, elution 0-5% ethyl acetate and petroleum ether) to get1-bromo-2-fluoro-4-iodo-5-methoxybenzene (720 g, 87%), as off-whitesolid. TLC solvent system: 100% hexanes. Product's R_(f): 0.6. MS (ESI,positive ion) m/z: 331.0 (M+1). ¹H NMR (400 MHz, CDCl₃) δ 7.55 (d, J=7.2Hz, 1H), 6.95 (d, J=5.6 Hz, 1H), 3.89 (s, 3H).

Step 5: Ethyl(E)-3-(5-(Benzylthio)-2-((4-Bromo-5-Fluoro-2-Methoxyphenyl)Amino)Phenyl)Acrylate

To a solution of (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (300g, 958.1 mmol, 1.0 equiv) and 1-bromo-2-fluoro-4-iodo-5-methoxybenzene(348.0 g, 1051.6 mmol, 1.1 equiv) in toluene (2.5 L) was added Cs₂CO₃(468 g, 1436.3 mmol, 1.5 equiv, Spectrochem) and the mixture wasdegassed with nitrogen for 20 mins. Pd₂(dba)₃ (35 g, 38.2 mmol, 0.04equiv, Hindustan Platinum) and XantPhos (44.6 g, 76.4 mmol, 0.08 equiv,GLR) were added to the reaction mixture and the mixture was heated at110° C. for 5h. The reaction mixture was allowed to cool to roomtemperature, diluted with dichloromethane (2.0 L) and filtered throughCELITE® The filtrate was concentrated under reduced pressure to obtainthe initial product which was purified by stirring with 5% ethyl acetatein hexanes (3.0 L) for 30 min and filtered to obtain (E)-ethyl3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenyl)acrylate(350 g, 71%) as yellow solid. TLC solvent system: 30% ethyl acetate inhexanes. Product's R_(f): 0.5. MS (ESI, positive ion) m/z; 516.2 (M+1).¹H NMR (400 MHz, DMSO) δ 7.73-7.61 (m, 3H), 7.34-7.15 (m, 6H), 7.02 (d,J=11.4 Hz, 1H), 6.60 (d, J=21.2 Hz, 1H), 6.33 (d, J=14.1 Hz, 1H), 4.26(s, 2H), 4.16-4.09 (m, 2H), 3.81 (s, 3H), 1.22 (t, J=7.2 Hz, 3H). Note:NH proton not observed.

Step 6: 6-(Benzylthio)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)Quinolin-2(1H)-One

To a solution of (E)-ethyl3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)phenypacrylate(250.0 g, 484.0 mmol, 1.0 equiv) in methanol (2.5 L) was addedtri(n-butyl)phosphine (50% solution in ethyl acetate, 48.9 mL, 96.8mmol, 0.2 equiv, Spectrochem) and the reaction mixture was heated at 70°C. for 5 h. The reaction mixture was allowed to cool to rt, concentratedunder reduced pressure to obtain the initial product which was purifiedby stirring with 5% ethyl acetate in hexanes (1.0 mL) and filtered toobtain6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one(201.0 g, 88%) as off white solid. TLC solvent system: 30% ethyl acetatein hexanes. Product's R_(f): 0.3. MS (ESI, positive ion) m/z; 470.0(M+1). ¹H NMR (400 MHz, DMSO) δ 7.92 (d, J=9.1 Hz, 1H), 7.79 (d, J=1.7Hz, 1H), 7.65 (d, J=6.1 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.40-7.22 (m,6H), 6.68 (d, J=9.6 Hz, 1H), 6.56 (d, J=8.8 Hz, 1H), 4.24 (s, 2H), 3.69(s, 3H).

Steps 7+8: Perfluorophenyl1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonate

To a solution of6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)quinolin-2(1H)-one(250.0 g, 531.5 mmol, 1.0 equiv) in acetonitrile (2.5 L) were addedacetic acid (200 mL) and water (130 mL). The resulting mixture wascooled to 0° C. and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione(188.5 g, 956.7 mmol, 1.8 equiv, Aldrich) was added portion-wise over 20min keeping the internal temperature below 5° C. The resultingsuspension was stirred at 0-5° C. under nitrogen for 45 min. Then asolution of pentafluorophenol (127.2 g, 690.95 mmol, 1.3 equiv, Apollo)in acetonitrile (200 mL) was added over 5 min followed by NEt₃ (307.7mL, 2.12 mol, 4.0 equiv) over 20 min keeping the internal temperaturebelow 5° C. The mixture was continued to be stirred at 0-5° C. for 30min. Water (4.0 L) was added and extracted with ethyl acetate (2×2.0 L).The organic layer was washed with brine (1.0 L), dried over sodiumsulfate, filtered and concentrated under reduced pressure to obtain theinitial material which was purified by stirring with isopropylalcohol:hexanes (1:1, 1.0 L) and filtered to obtain racemicperfluorophenyl1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(190 g, 60%) as white solid. TLC solvent system: 30% ethyl acetate inpet ether, Product's R_(f): 0.4. MS (ESI, positive ion) m/z; 594.2(M+1). ¹H-NMR (400 MHz, DMSO) δ 8.60 (d, J=2.0 Hz, 1H), 8.26 (d, J=9.8Hz, 1H), 7.95 (dd, J=2.2, 9.1 Hz, 1H), 7.70 (t, J=8.6 Hz, 2H), 6.95-6.88(m, 2H), 3.72 (s, 3H).

Step 9:(P)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

Racemic perfluorophenyl1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonatewas separated via Chiralcel OJ column (40% MeOH/60% CO₂) to give(P)-perfluorophenyl1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonateand (M)-perfluorophenyl1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonateas pale yellow flocculent solids. Data for peak 1: m/z (ESI) 594.0(M+H)⁺. Data for peak 2: m/z (ESI) 594.0 (M+H)⁺.

Step 10:(P)-L-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A 250-mL round-bottom flask was charged with (P)-perfluorophenyl1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(11.34 g, 19.08 mmol) and N-(4-methoxybenzyl)isoxazol-3-amine (4.09 g,20.04 mmol), then purged with nitrogen. Tetrahydrofuran (191 mL) wasintroduced, and the resultant brown solution cooled to 0° C. A solutionof lithium bis(trimethylsilyl)amide (1.0 M in THF, 21.0 mL, 21.0 mmol)was added dropwise via syringe to the stirred reaction mixture over 10min. After 15 min, 1.0 N HCl (100 mL) was introduced and the resultantreaction mixture was allowed to warm to rt. The mixture was diluted withand EtOAc (100 mL) and the layers were separated, and the aqueous layerwas further extracted with EtOAc (2×100 mL). The combined organic layerswere then washed with brine (100 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas then purified by flash column chromatography (100-g BIOTAGE® column,eluent: gradient, 0 to 100% EtOAc in heptane with 10% CH₂Cl₂ as anadditive) to afford(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(9.54 g, 15.53 mmol, 81% yield) as a white amorphous solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 8.82 (d, J=2.0 Hz, 1H), 8.38 (d, J=2.3 Hz, 1H), 8.17(d, J=9.4 Hz, 1H), 7.76 (t, J=5.1 Hz, 1H), 7.68 (d, J=6.1 Hz, 1H), 7.63(d, J=8.5 Hz, 1H), 7.26 (d, J=7.9 Hz, 2H), 6.91-6.78 (m, 4H), 6.74 (d,J=2.0 Hz, 1H), 4.92 (s, 2H), 3.73-3.69 (m, 6H), 3.32 (s, 1H). m/z (ESI)615.1 (M+H)⁺.

Intermediate G: 1-Bromo-2-Chloro-4-Iodo-5-Methoxybenzene

To a solution of 2-bromo-1-chloro-4-methoxybenzene (500 g, 2258 mmol) indichloromethane (7500 mL) was added silver(I) trifluoromethanesulfonate(638 g, 2483 mmol) at ambient temperature under nitrogen environment.The reaction mixture was stirred for 20 mins at ambient temperature andiodine (630 g, 2483 mmol) was added. The reaction mixture was stirred atambient temperature for 16 h. The mixture was then diluted with DCM(4500 mL) and filtered through CELITE. The CELITE bed was washed withDCM (2×1.0 L). The filtrate was washed with 20% aqueous sodiumthiosulfate (5.0 L) and saturated aqueous sodium bicarbonate solution(5.0 L). The organic layer was dried over sodium sulfate, filtered andconcentrated under reduced pressure to obtain the initial product whichwas purified by column chromatography (silica gel; mesh size 60-120,elution 0-5% ethyl acetate and petroleum ether) to afford1-bromo-2-chloro-4-iodo-5-methoxybenzene (610 g, 1756 mmol, 78% yield)as off-white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.83 (s, 1H), 7.03 (s,1H), 3.89 (s, 3H).

Intermediate H: N-(4-Methoxybenzyl)Pyrimidin-2-Amine

In a 50-mL microwave vial were successively dissolved in EtOH (20 mL),2-chloropyrimidine (1.5 g, 13.10 mmol), (4-methoxyphenyl)methenamine(2.15 g, 15.72 mmol, 1.2 equiv), and triethylamine (2.65 g, 26.2 mmol,2.0 equiv). The reaction tube was sealed and irradiated in the cavity ofa microwave reactor at a ceiling temperature of 120° C. at 80 W maximumpower for 1 h. After the reaction mixture was cooled with an air flowfor 15 min, it was diluted with water (100 mL), extracted with CH₂Cl₂(2×150 mL) and dried over Na₂SO₄. The reaction mixture was diluted withwater (50 mL) and extracted with ethyl acetate (2×50 mL). The organicextract was washed with sat. aq. NaCl (1×50 mL) and dried over Na₂SO₄.The solution was filtered and concentrated in vacuo to give the initialproduct as a yellow oil. The initial product was absorbed onto a plug ofsilica gel and purified by chromatography through a Redi-Sep pre-packedsilica gel column (12 g), eluting with a gradient of 20% to 30% EtOAc inhexane, to provide N-(4-methoxybenzyl)pyrimidin-2-amine (1.5 g, 6.97mmol, 53% yield) as an off white solid. m/z (ESI) 216.2 (M+H)⁺.

Intermediate I:(P)-1-(4-Bromo-5-Chloro-2-Methoxyphenyl)-N-(4-Methoxybenzyl)-2-Oxo-N-(Pyrimidin-2-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

Step 1:(E)-3-(5-(Benzylthio)-2-((4-Bromo-5-Chloro-2-Methoxyphenyl)Amino)Phenyl)Acrylate

To a solution of ethyl (E)-3-(2-amino-5-(benzylthio)phenyl)acrylate (175g, 555.0 mmol) and 1-bromo-2-chloro-4-iodo-5-methoxybenzene (231.3 g,666.2, mmol) in toluene (1.5 L) was added cesium carbonate (357.5 g,1100 mmol) and the mixture was degassed with nitrogen for 20 mins.tris(dibenzylideneacetone)dipalladium(0) (12.5 g, 13.0 mmol) andXantPhos (15.8 g, 27.2 mmol, 0.05 equiv) were added to the reactionmixture and the mixture was heated at 110° C. for 5 h. The reactionmixture was allowed to cool to room temperature, diluted withdichloromethane (1.0 L) and filtered through CELITE. The filtrate wasconcentrated under reduced pressure to obtain the initial product whichwas purified by stirring with 5% ethyl acetate in hexane (1.5 L) for 30min and filtered to obtain ethyl(E)-3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenypacrylate(290 g, 85% yield) as yellow solid. m/z (ESI) 532.2 (M+H)⁺.

Step 2:6-(Benzylthio)-1-(4-Bromo-5-Chloro-2-Methoxyphenyl)Quinolin-2(1H)-One

To a solution of ethyl(E)-3-(5-(benzylthio)-2-((4-bromo-5-chloro-2-methoxyphenyl)amino)phenyl)acrylate(300.0 g, 5630.0 mmol) in methanol (3.0 L) was addedtri(n-butyl)phosphine (50% solution in ethyl acetate, 56.2 mL, 1126mmol) and the reaction mixture was heated at 70° C. for 5 h. Thereaction mixture was allowed to cool to room temperature, concentratedunder reduced pressure to obtain the initial product which was purifiedby stirring with 5% ethyl acetate in hexane (1.0 mL) and filtered toobtain6-(benzylthio)-1-(4-bromo-5-chloro-2-methoxyphenyl)quinolin-2(1H)-one(210.0 g, 76.6%) as an off white solid, m/z (ESI) 486.0 (M+H)⁺.

Step 3: Perfluorophenyl1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonate

To a solution of6-(benzylthio)-1-(4-bromo-5-chloro-2-methoxyphenyl)quinolin-2(1H)-one(400.0 g, 824.9 mmol) in acetonitrile (2.5 L) and THF (2.5 L) were addedacetic acid (1.0 L) and water (700 mL). The resulting mixture was cooledto 0° C. and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (292 g,1484.8 mmol) was added portionwise over 30 min keeping the internaltemperature below 5° C. The resulting suspension was stirred at 0° C.under nitrogen for 45 min. Then a solution of pentafluorophenol (197.4g, 1072.3 mmol) in acetonitrile (500 mL) was added over 5 min followedby triethylamine (477 mL, 3299 mmol) over 30 min keeping the internaltemperature below 5° C. The mixture was continued to be stirred at 0° C.for 50 min. Water (4.0 L) was added and extracted with ethyl acetate(3×2.0 L). The organic layer was washed with brine (2.0 L), dried oversodium sulfate, filtered and concentrated under reduced pressure toobtain the initial product which was purified by stirring with isopropylalcohol/hexane (1:1, 2.0 L) and filtered to obtain perfluorophenyl1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (360 g, 72%) as a white solid. m/z (ESI) 610.6(M+H)⁺.

Step 4: (P)-Perfluorophenyl1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonate& (M)-Perfluorophenyl1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonate

Perfluorophenyl 1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (156 g, 255 mmol) was purified via chiral SFCchromatography ((S,S) Whelk-O, 45% isopropanol) to afford(P)-perfluorophenyl1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(72.66 g, 93% yield) and (M)-perfluorophenyl1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(76.13 g, 98% yield) as white solids, m/z (ESI) 610.6 (M+H)⁺.

Step 5:(P)-1-(4-Bromo-5-Chloro-2-Methoxyphenyl)-N-(4-Methoxybenzyl)-2-Oxo-N-(Pyrimidin-2-YL)-1,2-Dihydroquinoline-6-Sulfonamide

N-(4-Methoxybenzyl)pyrimidin-2-amine (9.72 g, 45.1 mmol) and(P)-perfluorophenyl1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(25.06 g, 41.0 mmol) were added to a 500-mL flask. The flask was flushedwith N₂ stream then tetrahydrofuran (136 mL) was added and the reactionwas cooled to 2° C. under N₂. Sodium tert-pentoxide (30% solution inTHF, 197 mL, 492 mmol) was added over 30 min via addition funnelmaintaining internal temperature around 5° C., and the pale yellowsolution turned orange upon the addition. The reaction was stirred for30 min in the ice bath. The reaction was then quenched with sat. aq.NH₄Cl and diluted with EtOAc. The layers were separated and the waterlayer was extracted twice with EtOAc. The combined organics were driedwith Na₂SO₄, filtered, and evaporated. IPA was added and a whiteprecipitate crashed out. The solvent was evaporated to approximately 100mL then additional IPA was added and the reaction was stirred for 18 h.The slurry was filtered and the solid was washed with IPA.

The solid was taken up in 150 mL of MTBE and heated at 40° C. for 2hours. The slurry was cooled to ambient temperature and filtered toobtain a white solid. The impure material was dissolved in 500 mL of 10%MeOH/DCM and stirred with 500 mL of sat. aq. NaHCO₃ for 30 minutes. Thelayers were separated and the water layer was extracted twice with 10%MeOH/DCM. The combined organics layers were dried and evaporated. Thefiltrates from IPA and MTBE titrations were combined and loaded onto 25g silica cartridge and purified by column chromatography (RediSep RfGold 120 g column, gradient elution 10% to 50% 3:1 EtOAc:EtOH in heptanewith 10% dichloromethane additive). The pure product of the column andthe product from the NaHCO₃ extraction were combined to afford(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(16.94 g, 26.4 mmol, 64% yield) as a pale yellow foam. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.58 (d, J=4.9 Hz, 2H), 8.39 (d, J=2.1 Hz, 1H), 8.13 (d,J=9.6 Hz, 1H), 7.96 (dd, 2.3 Hz, 1H), 7.76 (s, 1H), 7.73 (s, 1H), 7.29(d, J=8.8 Hz, 2H), 7.13 (t, J=4.9 Hz, 1H), 6.87 (d, J=8.8 Hz, 2H), 6.78(d, J=9.6 Hz, 1H), 6.74 (d, J=9.1 Hz, 1H), 5.36 (s, 2H), 3.72 (s, 3H),3.71 (s, 3H). m/z (ESI, positive ion) 642.8 (M+H)⁺.

Intermediate J: N-(4-Methoxybenzyl)Pyridazin-3-Amine

To a 25-mL round-bottomed flask was added 4-methoxybenzaldehyde (1.00 g,7.34 mmol) and pyridazin-3-amine (0.838 g, 8.81 mmol) in tetrahydrofuran(10 mL). Then, titanium(IV) isopropoxide (6.46 mL, 22.03 mmol) wasadded, and the reaction mixture was stirred at 70° C. for 16 h. Then thereaction mixture was cooled to 0° C., and sodium borohydride (0.556 g,14.69 mmol) was added portionwise. The reaction mixture was then stirredfor 2 h at 0° C. The reaction mixture was diluted with water (20 mL) andfiltered. The filtrate was then extracted with EtOAc (3×50 mL). Theorganic extract was washed with sat. aq. NaCl (30 mL) and dried overNa₂SO₄. The solution was filtered and concentrated in vacuo to give theinitial product as a orange oil. The initial product was absorbed onto aplug of silica gel and purified by chromatography through a Redi-Seppre-packed silica gel column (40 g), eluting with 0% to 15% MeOH inCH₂Cl₂ to provide N-(4-methoxybenzyl)pyridazin-3-amine (0.680 g, 3.16mmol, 43.0% yield) as yellow solid. m/z (ESI, positive ion) 216.2(M+H)⁺.

Intermediate K:(P)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-N-(4-Methoxybenzyl)-2-Oxo-N-(Pyridazin-3-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

A 100-mL recovery flask containing perfluorophenyl(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(5.00 g, 8.41 mmol) and N-(4-methoxybenzyl)pyridazin-3-amine (1.902 g,8.83 mmol) was flushed with nitrogen and subsequently charged with THF(34 mL). The solution was cooled to 0° C., and sodium tert-pentoxide(8.4 mL, 11.78 mmol, 1.4 M in THF) was added slowly. The pale yellowsolution was stirred at 0° C. for 15 min, and then volatiles wereremoved in vacuo. Water was added to cause formation of a whiteprecipitate. This precipitate was isolated, dissolved indichloromethane, and treated with heptane to cause formation of(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide(4.20 g, 6.71 mmol, 80% yield) as a white precipitate. m/z (ESI,positive ion) 625.0 (M+H)⁺.

Intermediate L: Perfluorophenyl(P)-1-(4-Bromo-2-Methoxy-5-Methylphenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonate

Step 1: (E)-Ethyl3-(5-(Benzylthio)-2-((4-Bromo-2-Methoxy-5-Methylphenyl)Amino)Phenyl)Acrylate

A round-bottom flask was charged with (E)-ethyl3-(2-amino-5-(benzylthio)phenyl)acrylate (4.729 g, 15.09 mmol),1-bromo-4-iodo-5-methoxy-2-methylbenzene (5.18 g, 15.84 mmol), XantPhos(0.437 g, 0.754 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.345g, 0.377 mmol), cesium carbonate (9.83 g, 30.2 mmol), and toluene (30mL) were added. A reflux condenser was attached, and the mixture washeated to reflux. After 4 h, additional portions oftris(dibenzylideneacetone)dipalladium(0) (172 mg) and XantPhos (213 mg)were added. After 2 h, additional portions of cesium carbonate (ca. 2 g)and 1-bromo-4-iodo-5-methoxy-2-methylbenzene (600 mg) were added.Following an additional 30 min of reflux, the mixture was cooled andfiltered through CELITE. The filter pad was washed with EtOAc (3×). Thefiltrate was concentrated. The residue was concentrated from MeOH, andtaken up in MeOH. The resulting suspension was heated to boiling, thensonicated and cooled to RT. The mixture was filtered, and the collectedsolid was washed with MeOH (3×) and dried under a stream of N2 for 48 hto give (E)-ethyl3-(5-(benzylthio)-2-((4-bromo-2-methoxy-5-methylphenyl)amino)phenyl)acrylate(5.21 g, 10.17 mmol, 67.4% yield) as a bright-yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ ppm 7.75 (d, J=15.9 Hz, 1H), 7.66 (d, J=2.1 Hz, 1H),7.42 (s, 1H), 7.37-7.20 (m, 6H), 7.14 (s, 1H), 6.85 (d, J=8.5 Hz, 1H),6.62 (s, 1H), 6.51 (d, J=15.9 Hz, 1H), 4.23 (s, 2H), 4.15 (q, J=7.0 Hz,2H), 3.78 (s, 3H), 2.14 (s, 2H), 1.23 (t, J=7.1 Hz, 3H). m/z (ESI) 512.2(M+H)⁺.

Step 2:6-(Benzylthio)-1-(4-Bromo-2-Methoxy-5-Methylphenyl)Quinolin-2(1H)-One

A round-bottom flask was charged with (E)-ethyl3-(5-(benzylthio)-2-((4-bromo-2-methoxy-5-methylphenyl)amino)phenypacrylate(5.12 g, 9.99 mmol) and MeOH (50.0 mL) to give a yellow suspension.Sodium methoxide (25 wt % in MeOH, 0.432 mL, 1.998 mmol) was added. Areflux condenser was attached, and the flask was lowered into a 70° C.heating bath. After 1 h, additional portions of MeOH (25 mL) and sodiummethoxide solution (ca. 0.85 mL) were added in sequence. After 7 h, themixture was cooled and concentrated under vacuum. The residue waspurified by chromatography on silica gel (80-g Redi-Sep column, 25-gsilica gel loading column, loaded as a solution in MeOH-DCM, then elutedwith 25-75% EtOAc/heptane containing 10% DCM). The fractions containingproduct were combined and concentrated to give6-(benzylthio)-1-(4-bromo-2-methoxy-5-methylphenyl)quinolin-2 (1H)-one(4.233 g, 9.08 mmol, 91% yield) as a tan solid. m/z (ESI) 466.1 (M+H)+.

Step 3: Perfluorophenyl1-(4-Bromo-2-Methoxy-5-Methylphenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonate

A round-bottom flask was charged with6-(benzylthio)-1-(4-bromo-2-methoxy-5-methylphenyl)quinolin-2(1H)-one(4.23 g, 9.07 mmol), DCM (71.1 mL), acetic acid (2.67 mL), and water(1.778 mL) to give clear, light-brown solution. The flask was cooled inan ice-water bath for 10 min, then1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (3.66 g, 18.59 mmol)was added in one portion. After 40 min, an additional portion of oxidant(850 mg) was added. The mixture was stirred for another 20 min, then2,3,4,5,6-pentafluorophenol (2.504 g, 13.60 mmol) and triethylamine(5.06 mL, 36.3 mmol) were added in sequence. After 20 min, the mixturewas diluted with water. The layers were separated, and the aq. layer wasextracted with DCM. The combined organic extracts were dried over sodiumsulfate, filtered, and concentrated. The residue was purified bychromatography on silica gel (80-g Redi-Sep Gold column, 25-g silica gelloading column, 10-60% EtOAc/Heptane with 10% DCM) to affordperfluorophenyl1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(3.37 g, 5.71 mmol, 63% yield). m/z (ESI) 590.0 (M+H)⁺.

Step 4: Perfluorophenyl(P)-1-(4-Bromo-2-Methoxy-5-Methylphenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonate

Perfluorophenyl1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(22.896 g, 38.79 mmol) was purified using a (S,S) Whelk-O, 5×25 cmcolumn. The mobile phase was run under isocratic conditions;supercritical CO₂ with 50% dichloromethane; flow rate: 350 mL/min. Thefirst eluting peak was assigned perfluorophenyl(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(10.425 g). The second eluting peak was assigned perfluorophenyl(M)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(10.76 g). Data for peak 1: m/z (ESI) 590.0 (M+H)⁺. Data for peak 2: m/z(ESI) 590.0 (M+H)⁺.

Intermediate M:(P)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-N-(4-Methoxybenzyl)-2-Oxo-N-(Pyrimidin-2-YL)-1,2-Dihydroquinoline-6-Sulfonamide

A 250-mL round-bottom flask was sequentially charged withperfluorophenyl(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(2.00 g, 3.37 mmol), tetrahydrofuran (17 mL), andN-(4-methoxybenzyl)pyrimidin-2-amine (0.724 g, 3.37 mmol), and theresulting solution was cooled to 0° C. Lithium bis(trimethylsilyl)amide(3.70 mL, 3.70 mmol, 1.0 M in THF) was then added dropwise to thestirred reaction mixture. After 15 min, aqueous HCl solution (1.0 M, 100mL) and EtOAc (100 mL) were added to the reaction mixture, which wassubsequently allowed to warm to ambient temperature. The layers wereseparated, and the aqueous layer was extracted with EtOAc (2×100 mL).The combined organic layers were then washed with brine (100 mL), driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was then purified by flash column chromatography(100 g BIOTAGE® column, gradient elution 0-100% EtOAc:heptane with 10%dichloromethane as co-eluent) to afford(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(1.10 g, 1.76 mmol, 52% yield) as a white solid. m/z (ESI, positive ion)625.8 (M+H)⁺.

Intermediate N:(P)-1-(4-Bromo-2-Methoxy-5-Methylphenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

To a 0° C. solution of N-(4-methoxybenzyl)isoxazol-3-amine (83 mg, 0.407mmol) and perfluorophenyl(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(200 mg, 0.339 mmol) in tetrahydrofuran (1.7 mL) was added sodiumtert-pentoxide (30 wt % in THF, 176 μL, 0.440 mmol) slowly. The reactionwas stirred for 30 minutes at 0° C. After 30 min, the reaction mixturewas partitioned between ethyl acetate and saturated aqueous ammoniumchloride. The organic layer was concentrated, and the residue wastriturated with MTBE (2 mL) to provide(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(191 mg, 0.313 mmol, 92% yield) as a white powder. m/z (ESI, positiveion) 609.8 (M+H)⁺.

Intermediate O: N-(4-Methoxybenzyl)Oxazol-2-Amine

In a 250-mL flask, 1,3-oxazol-2-amine (5.00 g, 59.5 mmol) and4-anisaldehyde (10.53 g, 8.85 mL, 77 mmol) were heated in toluene (119mL) for 2 hours at 90° C. The reaction was cooled to ambienttemperature, and sodium triacetoxyhydroborate (18.91 g, 89 mmol) wasadded portion-wise. The yellow reaction was stirred for 18 hours. Thereaction was then quenched with water, the layers were separated, andthe water layer was extracted twice with dichloromethane. The combinedorganics were dried with Na₂SO₄, filtered, and concentrated. The residuewas loaded onto 25 g silica cartridge and purified by columnchromatography (RediSep Rf Gold 120 g column, gradient elution 10-50%EtOAc:heptane) to afford N-(4-methoxybenzyl)oxazol-2-amine (1.588 g,7.78 mmol, 13% yield) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm7.55 (br t, J=6.1 Hz, 1H), 7.39 (d, J=1.0 Hz, 1H), 7.24 (d, J=8.6 Hz,2H), 6.87 (d, J=8.6 Hz, 2H), 6.73 (d, J=1.0 Hz, 1H), 4.26 (d, J=6.2 Hz,2H), 3.72 (s, 3H). m/z (ESI, positive ion) 205.2 (M+H)⁺.

Intermediate P:(P)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-N-(4-Methoxybenzyl)-N-(Oxazol-2-YL)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

To a 0° C. solution of N-(4-methoxybenzyl)oxazol-2-amine (82 mg, 0.404mmol) and perfluorophenyl(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(200 mg, 0.337 mmol) in tetrahydrofuran (1.6 mL) was slowly added sodiumtert-pentoxide, (30 wt % in THF, 175 μL, 0.438 mmol). The reaction wasstirred for 30 minutes at 0° C. The reaction mixture was thenpartitioned between ethyl acetate and saturated aqueous ammoniumchloride. The organic layer was concentrated. The residue was purifiedby silica gel column chromatography (gradient elution 20-80% [3:1 ethylacetate/ethanol]:heptane with 10% dichloromethane as a co-eluent) toprovide(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(180 mg, 0.293 mmol, 87% yield) as a white powder. m/z (ESI, positiveion) 613.8 (M+H)⁺.

Intermediate Q:(P)-1-(4-Bromo-2-Methoxyphenyl)-N-(Isoxazol-3-YL)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

To a 0° C. solution of N-(4-methoxybenzyl)isoxazol-3-amine (128 mg,0.625 mmol) and perfluorophenyl(P)-1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(300 mg, 0.521 mmol) in tetrahydrofuran (2.6 mL) was slowly added sodiumtert-pentoxide (30 wt % in THF, 271 μL, 0.677 mmol) slowly. The reactionwas stirred for 30 minutes at 0° C. The reaction mixture was thenpartitioned between ethyl acetate and saturated aqueous ammoniumchloride. The organic layer was concentrated. The residue was trituratedwith MTBE to provide1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(350 mg, 0.587 mmol, >99% yield) as an off-white solid. m/z (ESI,positive ion) 595.8 (M+H)⁺.

Intermediate R:(P)-1-(4-Bromo-2-Methoxyphenyl)-N-(4-Methoxybenzyl)-2-Oxo-N-(Pyrimidin-2-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

The title compound was prepared according to the method and purificationprotocol of Intermediate R using N-(4-methoxybenzyl)pyrimidin-2-amine(134 mg, 0.625 mmol). This afforded1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(140 mg, 0.230 mmol, 44% yield) as an off-white solid. m/z (ESI,positive ion) 606.8 (M+H)⁺.

Intermediate S:(P)-1-(4-Bromo-2-Methoxy-5-Methylphenyl)-N-(4-Methoxybenzyl)-2-Oxo-N-(Pyrimidin-2-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

The title compound was prepared according to the method and purificationprotocol of Intermediate R using perfluorophenyl(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(200 mg, 0.339 mmol). This afforded(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(130 mg, 0.209 mmol, 62% yield) as a white solid. m/z (ESI, positiveion) 620.8 (M+H)⁺.

Intermediate T: N-(2,4-Dimethoxybenzyl)Oxazol-2-Amine

In a 250 mL flask, a mixture of 1,3-oxazol-2-amine (5.00 g, 59.5 mmol)and 2,4-dimethoxybenzaldehyde (10.87 g, 65.4 mmol) were heated intoluene (100 mL) at 90° C. for 1 h. The reaction was cooled to rt thentreated with sodium triacetoxyborohydride (18.91 g, 89 mmol). Themixture was stirred at 100° C. for 1 h, then at rt for 60 h. Additionalsodium triacetoxyborohydride (18.91 g, 89 mmol) was added and thereaction stirred at 100° C. for 2 h. The reaction was then cooled anddiluted with ethyl acetate (500 mL) and water (100 mL). The organiclayer was washed with saturated sodium bicarbonate solution (3×200 mL)and brine (2×100 mL) and dried over magnesium sulfate. The solvent wasremoved under reduced pressure to give a viscous brown oil, which wasflushed through a plug of silica gel, washing with 50% [3:1 ethylacetate:ethanol]:heptane. The filtrate was concentrated and thenpurified by flash chromatography (HP silica 220 g column, gradientelution 0-70% ethyl acetate: [9:1 heptane:DCM]) to affordN-(2,4-dimethoxybenzyl)oxazol-2-amine (1.18 g, 5.04 mmol, 8% yield) as apale yellow solid. m/z (ESI, positive ion) 235.2 (M+H)⁺.

Intermediate U:(P)-1-(4-Bromo-2-Methoxyphenyl)-N-(2,4-Dimethoxybenzyl)-N-(Oxazol-2-YL)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

To a 0° C. solution of N-(2,4-dimethoxybenzyl)oxazol-2-amine (146 mg,0.625 mmol) and perfluorophenyl(P)-1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(300 mg, 0.521 mmol) in tetrahydrofuran (2.6 mL) was slowly added sodiumtert-pentoxide (30 wt % in THF, 0.271 mL, 0.677 mmol). The reaction wasstirred for 30 minutes at 0° C. The reaction mixture was thenpartitioned between ethyl acetate and saturated aqueous sodiumbicarbonate. The organic layer was concentrated. The residue waspurified by silica gel column chromatography (gradient elution 40-100%ethyl acetate:heptane with 10% dichloromethane as a co-eluent) toprovide(P)-1-(4-bromo-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.200 g, 0.319 mmol, 61.3% yield) as a colorless oil. m/z (ESI,positive ion) 625.8 (M+H)⁺.

Intermediate V:(P)-1-(4-Bromo-2-Methoxy-5-Methylphenyl)-N-(4-Methoxybenzyl)-2-Oxo-N-(Pyridazin-3-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

To a 0° C. solution of N-(4-methoxybenzyl)pyridazin-3-amine (0.219 g,1.02 mmol) and perfluorophenyl(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(0.5 g, 0.847 mmol) in tetrahydrofuran (4.2 mL) was slowly added sodiumtert-pentoxide (30 wt % solution in THF, 0.41 mL, 1.0 mmol). Thereaction was stirred for 30 minutes at 0° C. The reaction mixture wasthen partitioned between ethyl acetate and saturated aqueous ammoniumchloride. The organic layer was concentrated. The residue was purifiedby silica gel column chromatography (gradient elution 40-100% ethylacetate:heptane with 10% dichloromethane as a co-eluent) to provide(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide(367 mg, 0.591 mmol, 70% yield) as a white solid. m/z (ESI, positiveion) 620.8 (M+H)⁺.

Intermediate W:(P)-1-(4-Bromo-5-Chloro-2-Methoxyphenyl)-N-(2,4-Dimethoxybenzyl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

N-(2,4-dimethoxybenzyl)oxazol-2-amine (0.211 g, 0.901 mmol) andperfluorophenyl(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(0.500 g, 0.819 mmol, Syngene) were added to a 40-mL vial. The vial wasflushed with nitrogen, tetrahydrofuran (2.7 mL) was added, and then thereaction was cooled to 0° C. Sodium tert-pentoxide (3.2 M in PhMe, 0.33mL, 1.1 mmol) was added slowly. After stirring for 30 min at ° C., sat.aq. ammonium chloride and EtOAc were added to the cold reaction. Thephases were separated, and the water phase was extracted twice withEtOAc. The combined organic extracts were dried and evaporated. Theresidue was purified by column chromatography (two sequential RediSep RfGold 40 g columns, gradient elution 0-40% [3:1 EtOAc:EtOH]:[10:1heptane:dichloromethane]) to provide(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.347 g, 0.525 mmol, 64% yield) as a yellow solid. m/z (ESI, positiveion) 681.8 (M+Na)⁺.

Intermediate X:(P)-1-(4-Bromo-2-Methoxyphenyl)-N-(4-Methoxybenzyl)-2-Oxo-N-(Pyridazin-3-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

In a 250-mL flask, perfluorophenyl(P)-1-(4-bromo-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(7.00 g, 12.15 mmol) and N-(4-methoxybenzyl)pyridazin-3-amine (3.14 g,14.58 mmol) were suspended in tetrahydrofuran (100 mL). The pale brownsuspension was cooled in an ice bath and treated dropwise with sodiumtert-pentoxide (40 wt % in toluene, 7.77 mL, 19.43 mmol). The reactionwas stirred at 0° C. for 30 min and allowed to warm to rt. After 2 h,additional base sodium tert-pentoxide (40 wt % in toluene, 1 mL) wasadded, and the reaction stirred at rt for an additional 15 h. Additionaltert-pentoxide (40 wt % in toluene, 1 mL) was added, and the reactionstirred at rt for an additional 2 h. The reaction was cooled in an icebath and quenched with saturated ammonium chloride solution (50 mL), andthe reaction stirred vigorously for 15 min. The phases were separated,and the aqueous phase was extracted with ethyl acetate (3×50 mL). Theresidue was purified via silica gel column chromatography (gradientelution 0-100% [3:1 EtOAc:EtOH]: [9:1 heptane:dichloromethane]). Theproduct was further purified by trituration with ethyl acetate:heptane(1:1) to give(P)-1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide(1.56 g, 2.57 mmol, 21% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 9.04 (dd, J=4.5, 1.7 Hz, 1H), 8.26 (d, J=2.3 Hz, 1H),8.16 (d, J=9.3 Hz, 1H), 7.67-7.77 (m, 2H), 7.64 (dd, J=9.1, 2.3 Hz, 1H),7.53 (d, J=1.8 Hz, 1H), 7.35-7.40 (m, 1H), 7.30-7.34 (m, 1H), 7.15 (d,J=8.8 Hz, 2H), 6.76-6.85 (m, 3H), 6.72 (d, J=9.1 Hz, 1H), 5.03 (s, 2H),3.72 (s, 3H), 3.66 (s, 3H). m/z (ESI, positive ion) 607.0 (M+H)⁺.

Intermediate Y:(P)-1-(4-Bromo-5-Chloro-2-Methoxyphenyl)-N-(4-Methoxybenzyl)-2-Oxo-N-(Pyridazin-3-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

The title compound was prepared according to the method and purificationprotocol of Intermediate V using perfluorophenyl(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate(5.00 g, 8.19 mmol). This afforded(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide(2.84 g, 4.42 mmol, 54% yield). m/z (ESI, positive ion) 641.0 (M+H)⁺.

Intermediate Z:(P)-1-(4-Bromo-2-Methoxy-5-Methylphenyl)-N-(2,4-Dimethoxybenzyl)-N-(Oxazol-2-YL)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

The title compound was prepared according to the method of IntermediateN using N-(2,4-dimethoxybenzyl)oxazol-2-amine (0.236 g, 1.01 mmol). Theproduct was purified via column chromatography (two sequential RediSepRf Gold 40 g columns, gradient elution 0-40% [3:1 EtOAc:EtOH]: [9:1heptane:dichloromethane]) to afford(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.38 g, 0.59 mmol, 65% yield). ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm7.92 (d, J=2.1 Hz, 1H), 7.86 (dd, J=9.0, 2.2 Hz, 1H), 7.69 (d, J=9.6 Hz,1H), 7.46 (d, J=0.8 Hz, 1H), 7.33 (s, 1H), 7.16 (d, J=8.3 Hz, 1H), 7.08(s, 1H), 7.01 (d, J=0.8 Hz, 1H), 6.82 (d, J=9.6 Hz, 1H), 6.68 (d, J=9.1Hz, 1H), 6.37 (dd, J=8.3, 2.3 Hz, 1H), 6.17 (d, J=2.3 Hz, 1H), 4.94 (s,2H), 3.74 (s, 3H), 3.73 (s, 3H), 3.44 (s, 3H), 2.40 (s, 3H).

Intermediate AB: (3-(Trifluoromethyl)Bicyclo[1.1.1]Pentan-1-Yl)Zinc(II)Iodide

An oven-dried vial was charged with1-iodo-3-(trifluoromethyl)bicyclo[1.1.1]pentane (100 mg, 0.382 mmol),purged with nitrogen, and was added Rieke zinc, 5% in tetrahydrofuran(27 mg, 0.549 mL, 0.420 mmol). The mixture was stirred at roomtemperature for 3 hours. The resulting suspension was allowed to settledown. The product was used without further purification.

Intermediate AC: (P)-Perfluorophenyl1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-7-Fluoro-2-Oxo-1,2-Dihydroquinoline-6-Sulfonate

Step 1: 4-Bromo-5-Fluoro-2-Iodoaniline

N-iodosuccinimide (710 g, 3158 mmol) was added portion-wise to asolution of 4-bromo-3-fluoroaniline (500 g, 2631 mmol) in acetic acid(4000 mL) at 10-15° C. The reaction was stirred at rt for 1 hour. Thereaction was then quenched with ice water (7 L) and the precipitatedsolid was filtered. The solid was washed with 5% sodium thiosulphatesolution (6 L) and water (4 L), and dried to afford4-bromo-5-fluoro-2-iodoaniline as brown solid (750 g, 2374 mmol, 90%yield). ¹H NMR (400 MHz, DMSO-d6): δ ppm 7.76 (d, J=7.8 Hz, 1H), 6.68(d, J=11.5 Hz, 1H), 5.68 (s, 2H).

Step 2: Ethyl (E)-3-(2-Amino-5-Bromo-4-Fluorophenyl)Acrylate

To a stirred solution of 4-bromo-5-fluoro-2-iodoaniline (500 g, 1583mmol) in isopropanol (2550 mL) was added triethylamine (331 mL, 2374mmol) at room temperature. The reaction mixture was degassed withnitrogen for 20 minutes. Tris(dibenzylideneacetone)dipalladium (0) (36.2g, 39.6 mmol) was added, followed by slow addition of ethyl acrylate(162 g, 1614 mmol) under nitrogen atmosphere. Then the reaction mixturewas heated to 70° C. and stirred for 6 hours. After completion, thereaction mixture was filtered through Celite and washed withdichloromethane (2 L). The filtrate was concentrated under reducedpressure to give the initial product. The initial product was stirred in3% ethyl acetate in petroleum ether (6 L) and filtered. The solidobtained was washed with 3% EtOAc in petether (2 L) and dried to giveethyl (E)-3-(2-amino-5-bromo-4-fluorophenyl)acrylate (433 g, 1505 mmol,95% yield) as a yellow solid. MS (ESI, positive ion) m/z: 288.0 (M+1).¹H NMR (400 MHz, DMSO-d6): δ ppm 7.69-7.98 (m, 2H), 6.61 (d, J=11.4 Hz,1H), 6.45 (d, J=15.6 Hz, 1H), 6.12 (s, 2H), 4.17 (q, J=7.1 Hz, 2H), 1.26(t, J=7.1 Hz, 3H).

Step 3: Ethyl (E)-3-(2-Amino-5-(Benzylthio)-4-Fluorophenyl)Acrylate

To a solution of ethyl (E)-3-(2-amino-5-bromo-4-fluorophenyl)acrylate(500.0 g, 1735 mmol) in 1,4-dioxane (2500 mL) was addedN-ethyl-N-isopropylpropan-2-amine (449 g, 3471 mmol) and degassed withnitrogen for 20 minutes.(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (50.2 g, 87mmol) and tris(dibenzylideneacetone)dipalladium (0) (39.7 g, 43.4 mmol)were added to the reaction mixture. The mixture was purged with nitrogenand heated to 80° C. for 10 minutes. The reaction was cooled to roomtemperature and phenylmethanethiol (237 g, 1909 mmol) was added. Thereaction was heated at 90° C. for 12 hours. The reaction was cooled toroom temperature and diluted with ethyl acetate (1000 mL). The mixturewas filtered through Celite and the Celite bed was washed with ethylacetate (2500 mL). The filterate was concentrated under reduced pressureto obtain the initial product. The initial product was purified bycolumn chromatography (silica gel; mesh size 60-120, gradient elution0-15% ethyl acetate and petroleum ether) to obtain ethyl(E)-3-(2-amino-5-(benzylthio)-4-fluorophenyl)acrylate (300.0 g, 905mmol, 52% yield) as yellow solid. MS (ESI, positive ion) m/z: 332.1(M+1). ¹H NMR (400 MHz, DMSO-d6): δ ppm 7.72 (d, J=15.7 Hz, 1H), 7.41(d, J=8.5 Hz, 1H), 7.01-7.32 (m, 5H), 6.38-6.55 (m, 1H), 6.24 (d, J=15.7Hz, 1H), 6.11 (s, 2H), 4.17 (q, J=7.1 Hz, 2H), 3.89-4.07 (m, 2H), 1.26(t, J=7.1 Hz, 3H).

Step 4: Ethyl(E)-3-(5-(Benzylthio)-2-((4-Bromo-5-Fluoro-2-Methoxyphenyl)Amino)-4-Fluorophenyl)Acrylate

To a 250 mL 3-neck round-bottomed flask charged with ethyl(E)-3-(2-amino-5-(benzylthio)-4-fluorophenyl)acrylate (10 g, 30.2 mmol)and 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (10.48 g, 31.7 mmol) intoluene (100 mL) was added cesium carbonate (39.3 g, 121 mmol). Themixture was degassed with nitrogen for 15 minutes.Tris(dibenzylideneacetone)dipalladium (0) (1.105 g, 1.207 mmol) and(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (1.397 g,2.414 mmol) were added to the reaction mixture and the mixture washeated at 110° C. for 16 hours. The reaction mixture was allowed to coolto room temperature, diluted with dichloromethane (200 mL) and filteredthrough Celite. The filtrate was concentrated under reduced pressure toobtain the initial product which was purified by stirring with methanol(250 mL) for 1 hour and filtered. The cake was washed with methanol (100mL) and dried to obtain ethyl(E)-3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)-4-fluorophenyl)acrylate(13.5 g, 25.3 mmol, 84% yield) as yellow solid. MS (ESI, positive ion)m/z: 534.0 (M+1). ¹H NMR (400 MHz, DMSO-d6): δ ppm 7.97 (s, 1H), 7.75(d, J=8.4 Hz, 1H), 7.66 (d, J=15.9 Hz, 1H), 7.05-7.43 (m, 6H), 6.77 (d,J=11.1 Hz, 1H), 6.63 (d, J=10.2 Hz, 1H), 6.52 (d, J=15.9 Hz, 1H), 4.25(s, 2H), 4.16 (q, J=7.1 Hz, 2H), 3.82 (s, 3H), 1.23 (t, J=7.1 Hz, 3H).

Step 5:6-(Benzylthio)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-7-Fluoroquinolin-2(1H)-One

To 500 mL 3-necked round-bottom flask was charged with ethyl(E)-3-(5-(benzylthio)-2-((4-bromo-5-fluoro-2-methoxyphenyl)amino)-4-fluorophenypacrylate(13.5 g, 25.3 mmol) in methanol (140 mL) was added tributylphosphane(50% solution in ethylacetate) (3.74 mL, 7.58 mmol). The reactionmixture was heated at 70° C. for 5 hours. The reaction mixture wasallowed to cool 15° C., filtered and washed with cold methanol (100 mL)and dried to give6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoroquinolin-2(1H)-one(9.5 g, 19.45 mmol, 77% yield) as yellow solid. MS (ESI, positive ion)m/z: 488.0 (M+1). ¹H NMR (400 MHz, DMSO-d6): δ ppm 7.88-8.02 (m, 2H),7.64 (d, J=6.3 Hz, 1H), 7.56 (d, J=8.6 Hz, 1H), 7.20-7.38 (m, 5H), 6.64(d, J=9.6 Hz, 1H), 6.48 (d, J=11.3 Hz, 1H), 4.23 (s, 2H), 3.71 (s, 3H).

Step 6 & 7: Perfluorophenyl1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-7-Fluoro-2-Oxo-1,2-Dihydroquinoline-6-Sulfonate

To a 250 mL 3-necked round-bottom flask charged with6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoroquinolin-2(1H)-one(9.5 g, 19.45 mmol) in acetonitrile (95 mL) were added acetic acid (6.4mL) and water (4.13 mL). The resulting mixture was cooled to 0-5° C. and1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (6.13 g, 31.1 mmol) wasadded portion-wise over 10-20 min keeping the internal temperature below5-10° C. The resulting suspension was stirred at 5-10° C. under nitrogenfor 45 minutes. Then a solution of 2,3,4,5,6-pentafluorophenol (7.16 g,38.9 mmol) in acetonitrile (10 mL) was added over 10-15 min, followed bytriethylamine (13.54 mL, 97 mmol) over 20 min keeping the internaltemperature below 5-10° C. The mixture was continued to be stirred at5-10° C. for 30 min. Ice water (200 mL) was added and the precipitatedsolid was filtered and washed with water (100 mL). The initial productwas purified by stirring with methanol (50 mL), filtered, washed withMeOH (50 mL) and dried to obtain perfluorophenyl1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate(9.5 g, 15.52 mmol, 80% yield) as an off white solid. MS (ESI, positiveion) m/z; 612.0 (M+1). ¹H NMR (400 MHz, DMSO-d6): δ ppm 8.53 (d, J=7.4Hz, 1H), 8.20 (d, J=9.8 Hz, 1H), 7.67 (dd, J=16.2, 7.4 Hz, 2H), 6.99 (d,J=12.1 Hz, 1H), 6.83 (d, J=9.8 Hz, 1H), 3.74 (s, 3H).

Step 8: (P)-Perfluorophenyl1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-7-Fluoro-2-Oxo-1,2-Dihydroquinoline-6-Sulfonate

Perfluorophenyl1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate(135 g, 220 mmol) was purified by SFC via an Regis Whelk-O s,s 5×15 cm,5 μm column; a mobile phase of 50% dichloromethane using a flowrate of350 mL/min to generate (P)-perfluorophenyl1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate(49.2 g, 80.4 mmol, 36% yield). MS (ESI, positive ion) m/z: 612.7 (M+1).

CHEMICAL EXAMPLES Examples 1 & 2:(M)-1-(4-(3-(Tert-Butyl)Cyclobutyl)-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamideand1-(4-(3-(Tert-Butyl)Cyclobutyl)-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide,Respectively

Step 1:(M)-1-(4-(3-(Tert-Butyl)Cyclobutyl)-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A vial was charged with palladium(II) acetate (2.7 mg, 0.012 mmol),2′-(dicyclohexylphosphino)-N²,N²,N⁶,N⁶-tetramethyl-[1,1′-biphenyl]-2,6-diamine(10.6 mg, 0.024 mmol), and(M)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.100 g, 0.202 mmol). (3-(tert-butyl)cyclobutyl)zinc(II) iodide (0.2 Min THF, 2.0 mL, 0.41 mmol) was added and the reaction was stirred fortwo hours at 50° C. The reaction was then diluted with ethyl acetate andwashed twice with 1 N HCl. The organic layer was washed with brine,dried with sodium sulfate, filtered, and concentrated. The material waspurified via column chromatography (RediSep Gold 40 g column, gradientelution 0-50% [3:1 EtOAc:EtOH]:heptane) to give(M)-1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(50 mg, 0.095 mmol, 47% yield) as a mixture of cis and trans isomers. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 11.65 (s, 1H), 8.73 (d, J=1.9 Hz, 1H),8.30-8.41 (m, 1H), 8.20 (d, J=10.0 Hz, 1H), 7.72-8.00 (m, 1H), 7.04-7.29(m, 2H), 6.73-6.85 (m, 2H), 6.44 (d, J=1.5 Hz, 1H), 3.64-3.75 (m, 3H),3.45-3.63 (m, 1H), 2.18-2.38 (m, 4H), 1.89-2.04 (m, 1H), 0.83-0.97 (m,9H). m/z (ESI, positive ion) 526.2 (M+H)⁺.

Step 2:1-(4-(3-(Tert-Butyl)Cyclobutyl)-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

(M)-1-(4-(3-(tert-Butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(44 mg) was epimerized by heating at 130° C. for 3 h in DMSO. This wasthen concentrated and dried to give1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.66 (s, 1H), 8.74 (d, J=1.7 Hz, 1H),8.31-8.41 (m, 1H), 8.14-8.30 (m, 1H), 7.75-7.93 (m, 1H), 7.03-7.32 (m,2H), 6.74-6.84 (m, 2H), 6.45 (d, J=1.5 Hz, 1H), 3.70 (d, J=10.0 Hz, 3H),3.57-3.64 (m, 1H), 2.19-2.41 (m, 4H), 1.91-2.06 (m, 1H), 0.86-0.96 (m,9H). m/z (ESI, positive ion) 526.2 (M+H)⁺.

Example 3:(P)-1-(4-(3-(Tert-Butyl)Cyclobutyl)-5-Fluoro)-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-DihydroQuino Line-6-Sulfonamide

A vial was charged with palladium(II) acetate (7.3 mg, 0.032 mmol)2′-(dicyclohexylphosphino)-N²,N²,N⁶,N⁶-tetramethyl-[1,1′-biphenyl]-2,6-diamine(28 mg, 0.065 mmol), and(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(160 mg, 0.324 mmol). (3-(tert-Butyl)cyclobutyl)zinc(II) iodide (0.2 Min THF, 3.2 mL, 0.65 mmol) was added, and the reaction was stirred fortwo hours at 50° C. The reaction was then diluted with ethyl acetate andwashed twice with 1 N HCl. The organic layer was washed with brine,dried with sodium sulfate, filtered, and concentrated. The material waspurified via column chromatography (RediSep Gold 40 g column, gradientelution 0-50% [3:1 EtOAc:EtOH]:heptane) to give(P)-1-(4-(3-(tert-butyl)cyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(90 mg, 0.17 mmol, 53% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.65 (s,1H), 8.72 (d, J=1.9 Hz, 1H), 8.29-8.38 (m, 1H), 8.20 (d, J=10.0 Hz, 1H),7.84 (dt, J=9.0, 1.9 Hz, 1H), 7.03-7.33 (m, 2H), 6.71-6.85 (m, 2H), 6.44(d, J=1.7 Hz, 1H), 3.69 (d, J=10.2 Hz, 3H), 3.53-3.63 (m, 1H), 2.16-2.37(m, 4H), 1.91-2.07 (m, 1H), 0.80-0.95 (m, 9H). m/z (ESI, positive ion)526.2 (M+H)⁺.

Example 4: (P)-1-(4-(3,3-DifluoroCyclobutyl)-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-DihydroQuinoline-6-Sulfonamide

Step 1:(P)-1-(5-Fluoro-2-Methoxy-4-(5,8-Dioxaspiro[3.4]Octan-2-Yl)Phenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A vial was charged with(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(Intermediate F) (0.500 g, 0.814 mmol), palladium(II) acetate (10.96 mg,0.049 mmol), and2′-(dicyclohexylphosphino)-N²,N²,N⁶,N⁶-tetramethyl-[1,1′-biphenyl]-2,6-diamine(0.043 g, 0.098 mmol). 5,8-Dioxaspiro[3.4]octan-2-ylzinc(II) bromide(0.1 M in THF, 14 mL, 0.70 mmol) was added and the reaction was stirredat 50° C. for 16 h. The reaction was then diluted with ethyl acetate andwashed with water. The aqueous layer was extracted with ethyl acetate,and the combined organic layers were washed with brine, dried withsodium sulfate, filtered, and concentrated. The material was purifiedvia column chromatography (RediSep Gold 40 g column, gradient elution0-100% EtOAc:heptane) to afford(P)-1-(5-fluoro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.258 g, 0.398 mmol, 49% yield) as a light yellow solid. m/z (ESI,positive ion) 648.2 (M+H)⁺.

Step 2:(P)-1-(5-Fluoro-2-Methoxy-4-(3-Oxocyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

(P)-1-(5-Fluoro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.258 g, 0.398 mmol) was dissolved in tetrahydrofuran (4 mL).Hydrochloric acid (1 N in water, 2.0 mL, 2.0 mmol) was added and thereaction was stirred at 50° C. for three days. The reaction was thendiluted with ethyl acetate and washed with water. The aqueous layer wasextracted with ethyl acetate, and the combined organic layers werewashed with brine, dried with sodium sulfate, filtered, andconcentrated. The material was purified via column chromatography(RediSep Gold 40 g column, gradient elution 0-100% EtOAc:heptane) toafford(P)-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.179 g, 0.297 mmol, 74% yield) as a light yellow solid. m/z (ESI,positive ion) 604.2 (M+H)⁺.

Step 3:(P)-1-(4-(3,3-Difluorocyclobutyl)-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A vial was charged with(P)-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.169 g, 0.280 mmol) and diethylaminosulfur trifluoride (1.85 mL, 14.0mmol). The reaction was stirred for one hour at room temperature. Thereaction was then poured into a 250-mL round-bottom flask, diluted withethyl acetate, and saturated aqueous sodium bicarbonate solution wascarefully added until bubbling ceased. The layers were separated, andthe aqueous layer was extracted with ethyl acetate. The combined organiclayers were washed with brine, dried with sodium sulfate, filtered, andconcentrated. The material was purified via column chromatography(RediSep Gold 12 g column, gradient elution 0-100% EtOAc:heptane) toafford(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.142 g, 0.227 mmol, 81% yield) as a white solid. m/z (ESI, positiveion) 626.2 (M+H)⁺.

Step 4:(P)-1-(4-(3,3-Difluorocyclobutyl)-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

(P)-1-(4-(3,3-Difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.142 g, 0.227 mmol) was dissolved in TFA (1 mL). The solution washeated to 50° C. and stirred for two hours. The reaction wasconcentrated and purified via column chromatography (RediSep Gold 40 gcolumn, gradient elution 0-75% [3:1 EtOAc/EtOH]:heptane) to afford(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.109 g, 0.216 mmol, 95% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.66 (s, 1H), 8.74 (d, J=1.9 Hz, 1H), 8.37 (d, J=2.3 Hz,1H), 8.22 (d, J=9.5 Hz, 1H), 7.84 (dd, J=8.9, 2.3 Hz, 1H), 7.36 (d,J=10.2 Hz, 1H), 7.27 (d, J=6.8 Hz, 1H), 6.76-6.84 (m, 2H), 6.45 (d,J=1.7 Hz, 1H), 3.71 (s, 3H), 3.57-3.68 (m, 1H), 2.91-3.13 (m, 4H). m/z(ESI, positive ion) 506.0 (M+H)⁺.

Example 5:(P)-1-(5-Fluoro-4-(3-Fluoro-3-(Trifluoromethyl)Cyclobutyl)-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

Step 1:(P)-1-(5-Fluoro-4-(3-Hydroxy-3-(Trifluoromethyl)Cyclobutyl)-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A round-bottom flask was charged with(P)-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.500 g, 0.828 mmol) and THF (4.1 mL). Trifluoromethyltrimethylsilane(0.21 mL, 1.4 mmol) and tetra-n-butylammonium fluoride (1.0 M in THF,0.083 mL, 0.083 mmol) were added in succession, and the reaction wasstirred for one hour at room temperature. Additional(trifluoromethyl)trimethylsilane (0.208 ml, 1.408 mmol) andtetra-n-butylammonium fluoride (1.0 M in THF, 0.5 mL, 0.5 mmol) wereadded, and the reaction was stirred for 16 h. HCl (1 N in water, 5.8 mL,5.8 mmol) was added, and the reaction was stirred for one hour. Thereaction was then extracted twice with ethyl acetate. The combinedorganic layers were washed with brine, dried with sodium sulfate,filtered, and concentrated. The material was purified via columnchromatography (BIOTAGE® SNAP 25 g column, gradient elution 0-100%EtOAc:heptane) to afford(P)-1-(5-fluoro-4-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.433 g, 0.643 mmol, 78% yield) as a tan solid. m/z (ESI, positive ion)674.0 (M+H)⁺.

STEP 2:(P)-1-(5-Fluoro-4-(3-Fluoro-3-(Trifluoromethyl)Cyclobutyl)-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

To a vial charged with(P)-1-(5-fluoro-4-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.131 g, 0.194 mmol) was added bis(2-methoxyethyl)aminosulfurtrifluoride (1.0 mL, 5.4 mmol). The reaction was heated to 50° C. andstirred for 16 h. The reaction was diluted with ethyl acetate andcarefully quenched with saturated aqueous sodium bicarbonate solution.The aqueous layer was extracted with ethyl acetate, and the combinedorganic layers were washed with brine, dried with sodium sulfate,filtered, and concentrated. The material was purified via columnchromatography (RediSep Gold 12 g column, gradient elution 0-100%EtOAc:heptane) and then via reverse phase HPLC using a XBridge PrepShield RP18 19×100 mm column. The mobile was run under a gradientelution; 50-95% acetonitrile:water with 0.1% formic acid; flow rate: 40mL/min. This afforded(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.027 g, 0.040 mmol, 21% yield) as a white solid. m/z (ESI, positiveion) 676.0 (M+H)⁺.

Step 3:(P)-1-(5-Fluoro-4-(3-Fluoro-3-(Trifluoromethyl)Cyclobutyl)-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A vial was charged with(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.027 g, 0.040 mmol) and TFA (0.2 mL) and stirred overnight at roomtemperature. The reaction was then concentrated and purified via columnchromatography (BIOTAGE® SNAP 10 g column, gradient elution 0-75% [3:1EtOAc/EtOH]:heptane) to afford(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.018 g, 0.032 mmol, 81% yield) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 11.67 (s, 1H), 8.73 (d, J=1.7 Hz, 1H), 8.38 (d, J=2.1 Hz,1H), 8.23 (d, J=9.5 Hz, 1H), 7.85 (dd, J=8.9, 2.3 Hz, 1H), 7.41-7.53 (m,2H), 6.81 (d, J=9.7 Hz, 1H), 6.76 (d, J=9.1 Hz, 1H), 6.45 (d, J=1.9 Hz,1H), 5.95-6.22 (m, 2H), 5.86 (s, 1H), 3.64-3.80 (m, 3H), 3.07-3.21 (m,1H), 2.81-2.98 (m, 1H). m/z (ESI, positive ion) 556.0 (M+H)⁺.

Examples 6 & 7:Cis-(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-SulfonamideandTrans-(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide,Respectively

Step 1:(P)—O-(3-(2-Fluoro-4-(6-(N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)Sulfamoyl)-2-Oxoquinolin-1(2H)-Yl)-5-Methoxyphenyl)-1-(Trifluoromethyl)Cyclobutyl)O-Phenyl Carbonothioate

(P)-1-(5-Fluoro-4-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.200 g, 0.297 mmol), which was prepared according to proceduresdescribed in Steps 1-2 of Example 4 followed by Step 1 of Example 5, wasdissolved in THF (1.5 mL) and cooled to 0° C. Sodium hydride (60%dispersion in mineral oil, 0.018 g, 0.45 mmol) was added and thereaction was allowed to warm to room temperature over 30 minutes. Phenylchlorothionoformate (0.103 mL, 0.742 mmol) was added and the reactionwas stirred for three hours. The reaction was then cooled to 0° C. andan additional portion of sodium hydride (60% dispersion in mineral oil,0.018 g, 0.445 mmol) was added. The reaction was warmed to roomtemperature and stirred for 30 minutes, then additional phenylchlorothionoformate (0.103 mL, 0.742 mmol) was added. The reaction wasstirred at room temperature for 16 h. The reaction was then diluted withethyl acetate and washed with saturated aqueous sodium bicarbonatesolution. The aqueous layer was extracted with ethyl acetate, and thecombined organic layers were washed with brine, dried with sodiumsulfate, filtered, and concentrated. The material was purified viacolumn chromatography (BIOTAGE® SNAP 25 g column, gradient elution0-100% EtOAc:heptane) to afford(P)—O-(3-(2-fluoro-4-(6-(N-(isoxazol-3-yl)-N-(4-methoxybenzyl)sulfamoyl)-2-oxoquinolin-1(2H)-yl)-5-methoxyphenyl)-1-(trifluoromethyl)cyclobutyl)O-phenyl carbonothioate (0.215 g, 0.265 mmol, 89% yield) as a lightyellow solid.

Step 2:(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

(P)—O-(3-(2-Fluoro-4-(6-(N-(isoxazol-3-yl)-N-(4-methoxybenzyl)sulfamoyl)-2-oxoquinolin-1(2H)-yl)-5-methoxyphenyl)-1-(trifluoromethyl)cyclobutyl)-O-phenylcarbonothioate (0.119 g, 0.147 mmol) was dissolved in toluene (1.5 mL).Tri-n-butyl tin hydride (0.39 mL, 1.5 mmol) and azobisisobutyronitrile(0.024 g, 0.15 mmol) were added, and the reaction was degassed for 20minutes with nitrogen, then heated to 50° C. and stirred for two hours.The reaction was also run twice under the same conditions and reagentstoichiometry using04342-fluoro-4-(6-(N-(isoxazol-3-yl)-N-(4-methoxybenzyl)sulfamoyl)-2-oxoquinolin-1(2H)-yl)-5-methoxyphenyl)-1-(trifluoromethyl)cyclobutyl)0-phenyl carbonothioate (0.025 g, 0.031 mmol). All three reactions werethen combined, loaded onto a silica cartridge, and purified via columnchromatography (BIOTAGE® SNAP 25 g column, gradient elution 0-100%EtOAc:heptane) to afford(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.101 g, 0.154 mmol, 74% yield) as a light yellow solid. m/z (ESI,positive ion) 658.0 (M+H)⁺.

Step 3:Cis-(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-SulfonamideandTrans-(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A vial was charged with(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.101 g, 0.154 mmol) and TFA (1.0 mL) and stirred overnight at roomtemperature. The reaction was then concentrated and purified via columnchromatography (BIOTAGE® SNAP 10 g column, gradient elution 0-75% [3:1EtOAc/EtOH]:heptane) to afford 81 mg of material as an off-white solid.This material was further purified using two sequential Chiralcel OJ-H,2×25 cm columns. The mobile phase was run under isocratic conditions;supercritical CO₂ with 15% methanol; flow rate: 80 mL/min. The firsteluting peak was assignedcis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(39 mg). The second eluting peak was assignedtrans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(11 mg). Data for peak 1: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.65 (s, 1H),8.60-8.83 (m, 1H), 8.35 (d, J=2.1 Hz, 1H), 8.20 (d, J=9.6 Hz, 1H), 7.83(dd, J=9.0, 2.2 Hz, 1H), 7.31 (d, J=10.1 Hz, 1H), 7.14 (d, J=6.7 Hz,1H), 6.71-6.89 (m, 2H), 6.44 (d, J=1.8 Hz, 1H), 3.71-3.83 (m, 1H), 3.69(s, 3H), 3.24-3.31 (m, 1H), 2.56-2.65 (m, 2H), 2.31-2.44 (m, 2H). m/z(ESI, positive ion) 538.0 (M+H)⁺. Data for peak 2: ¹H NMR (500 MHz,DMSO-d₆) δ ppm 11.65 (s, 1H), 8.73 (d, J=1.8 Hz, 1H), 8.36 (d, J=2.3 Hz,1H), 8.21 (d, J=9.6 Hz, 1H), 7.84 (dd, J=9.0, 2.2 Hz, 1H), 7.24-7.40 (m,2H), 6.79 (d, J=9.6 Hz, 2H), 6.44 (d, J=1.6 Hz, 1H), 3.94 (quin, J=8.9Hz, 1H), 3.71 (s, 3H), 3.25-3.31 (m, 1H), 2.56-2.75 (m, 4H). m/z (ESI,positive ion) 538.0 (M+H)⁺.

Example 7a:Trans-(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

Step 1:(P)-1-(5-Fluoro-2-Methoxy-4-((1R,3R)-3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A 2 L three-neck round-bottom flask equipped with overhead stirrer,distillation head, thermocouple, addition funnel, and nitrogen inlet wascharged with zinc dust (112 g, 1.72 mol), lithium chloride (16.0 g, 389mmol), and anhydrous tetrahydrofuran (750 mL). Half of thetetrahydrofuran was removed via distillation at atmospheric pressure.The resultant mixture was cooled to 30° C. and chlorotrimethylsilane(3.0 mL, 23.5 mmol) was added. The mixture was warmed to 50° C. for 30minutes, the temperature was raised, and the reaction volume was reducedby about 50 mL via distillation. The resultant mixture was cooled to 30°C. before trans-1-bromo-3-(trifluoromethyl)cyclobutane (75.0 g, 369mmol, Enamine, LLC) was introduced. The mixture was then warmed to 40°C. A significant exotherm was observed and the heating mantle wasreplaced with an ambient temperature water bath. Once the exotherm hadceased, the water bath was removed and the reaction mixture stirred at50° C. for 1 hour. The mixture was allowed to settle overnight and coolto ambient temperature. The supernatant was used without furthermanipulation. A separate 2 L three-neck round-bottom flask equipped withoverhead stirrer, thermocouple, reflux condenser, and nitrogen inlet wascharged with 1,2,3,4,5-pentaphenyl-1′-(di-t-butylphosphino)ferrocene(0.90 g, 1.27 mmol, Strem Chemicals, Inc.),tris(dibenzylideneacetone)dipalladium (0.60 g, 0.66 mmol, StremChemicals, Inc.), and anhydrous tetrahydrofuran (50 mL). The resultantmixture was warmed to 45° C. After 15 minutes, the reaction mixture wasallowed to cool to room temperature before anhydrous tetrahydrofuran(250 mL) and(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(Intermediate F) (187 g, 304 mmol) were introduced and the mixture wasstirred until all solids dissolved. The resultant reaction mixture waswarmed to 40° C. before the supernatant from the previous reactioncontaining trans-3-(trifluoromethyl)cyclobutyl)zinc(II) bromide in THFwas added dropwise via cannula. The reaction was mildly exothermic andthe rate of addition was adjusted to keep the internal temperaturebetween 40-45° C. Once the addition was complete, the mixture was warmedto 50° C. After 3 hours, an aqueous solution of citric acid (1M, 400 mL)and water (500 mL) were introduced and the resultant mixture wasextracted with ethyl acetate (1500 mL). The organic layer was washedwith brine (500 mL) and concentrated under reduced pressure. Theresultant solid was suspended in isopropanol (1 L) and stirred at 40° C.for 20 minutes. The mixture was cooled to ambient temperature andfiltered through a sintered glass fritted filter. The solids were washedwith isopropanol (40 mL) and transferred to a 2 L round-bottomed flask.Isopropyl acetate (1 L) was added and the mixture stirred at 40° C. for20 minutes. The suspension was filtered through a sintered glass frittedfilter and the solids were washed with additional isopropyl acetate (50mL). The filtrate was transferred to a 2 L round-bottomed flask andSiliaMetS Thiol metal scavenger (20 g, Silicycle) and activated carbon(20 g) were added. The mixture stirred at ambient temperature for 20minutes. The suspension was filtered through a pad of Celite and thesolids washed with isopropyl acetate (500 mL). The filtrate wasconcentrated under reduced pressure. A mixture of dichloromethane andmethyl tert-butyl ether (1:1 mixture, 1 L) was added to the solids andthe resultant mixture stirred at 40° C. for 20 minutes. The mixture wasfiltered through a sintered glass fritted filter and the trace solidswere washed with methyl tert-butyl ether (30 mL). The combined filtratewas concentrated under reduced pressure to afford(P)-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(150 g, 228 mmol, 75% yield) as a reddish solid that was used in thenext step without further purification. m/z (ESI) 658.0 (M+H)⁺.

Step 2:(P)-1-(5-Fluoro-2-Methoxy-4-((1R,3R)-3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A 2 L three-neck round-bottom flask equipped with an overhead stirrer, aClaisen adapter, addition funnel, a thermocouple, a reflux condenser,and a nitrogen inlet was charged with(P)-1-(5-fluoro-2-methoxy-4-(1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(150 g, 228 mmol) and triethylsilane (85 mL, 532 mmol). Trifluoroaceticacid (500 mL) was added dropwise over 60 min at a rate to prevent theinternal temperature of the reaction exceeding 40° C.-50° C. Thereaction mixture was warmed to 50° C. for 30 min before it was allowedto cool to room temperature. Heptane (800 mL) was introduced and themixture was concentrated under reduced pressure. The resultant solid wasazeotroped with heptane (2×800 mL) then suspended in heptane (800 mL).The mixture was stirred at ambient temperature for 10 minutes before theheptane was decanted away. The remaining material was dissolved indichloromethane (1.5 L) and was washed with an aqueous solution oftribasic sodium phosphate (0.2 N, 2×300 mL). The organic layer wasseparated and concentrated under reduced pressure. The residue wassuspended in methyl tert-butyl ether (2 L) and stirred at 40° C. for 20minutes. The suspension was filtered through a sintered glass frittedfilter and the solids washed with methyl tert-butyl ether (100 mL). Thefiltrate was evaporated to dryness under reduced pressure and theproduct was suspended in methanol (500 mL). The resultant suspension wasconcentrated under reduced pressure and the residue was purified via SFCin two steps (Step 1: Waters Torus 2-PIC, 5 μM, 3×15 cm column using 25%methanol as an eluent at 180 mL/min flow rate; Step 2: Chiralcel OJ-H, 5μm, 5×40 cm column using 20% methanol as an eluent at 240 mL/min flowrate) to afford(P)-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(63.3 g, 118 mmol, 52% yield). ¹H NMR (500 MHz, CDCl₃) δ: 8.58 (s, 1H),8.26 (s, 1H), 8.16 (d, J=1.8 Hz, 1H), 7.78 (t, J=9.9 Hz, 2H), 6.92-6.98(m, 2H), 6.86 (d, J=9.6 Hz, 1H), 6.77 (d, J=9.0 Hz, 1H), 6.59 (s, 1H),3.98 (quin, J=9.0 Hz, 1H), 3.72-3.80 (m, 3H), 2.99-3.11 (m, 1H),2.69-2.74 (m, 2H), 2.60-2.65 (m, 2H). ¹³C NMR (126 MHz, CDCl₃) δ:161.57, 159.89, 156.85, 154.94 (d, J=241.6 Hz), 151.41 (d, J=2.7 Hz),143.79, 139.41, 133.89 (d, J=15.4 Hz), 132.62, 128.19, 128.30 (q,J=276.1 Hz), 124.00, 123.34, 120.04, 117.16 (d, J=25.4 Hz), 116.42,111.73 (d, J=5.5 Hz), 98.59, 56.39, 34.01 (q, J=30.0 Hz), 31.80, 27.76,27.50, 27.31. m/z (ESI) 538.0 (M+H)⁺.

Examples 8 and 9:Trans-(P)-1-(5-Fluoro-4-(3-Fluoro-3-(Trifluoromethyl)Cyclobutyl)-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-SulfonamideandCis-(P)-1-(5-Fluoro-4-(3-Fluoro-3-(Trifluoromethyl)Cyclobutyl)-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide,Respectively

A vial was charged with(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.212 g, 0.314 mmol) and TFA (1 mL) and stirred at 50° C. for twohours. The reaction was then concentrated and purified using twosequential Chiralpak IC, 2×15 cm columns. The mobile phase was run underisocratic conditions; supercritical CO₂ with 25% methanol; flow rate: 80mL/min. The first eluting peak was assignedtrans-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(62 mg). The second eluting peak was assignedcis-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(42 mg). Data for peak 1: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.65 (s, 1H),8.73 (d, J=1.7 Hz, 1H), 8.37 (d, J=2.3 Hz, 1H), 8.22 (d, J=9.5 Hz, 1H),7.84 (dd, J=8.9, 2.3 Hz, 1H), 7.49 (d, J=10.2 Hz, 1H), 7.44 (d, J=6.2Hz, 1H), 6.79 (dd, J=9.2, 5.7 Hz, 2H), 6.44 (d, J=1.9 Hz, 1H), 5.95-6.14(m, 2H), 5.85 (s, 1H), 3.71 (s, 3H), 3.15 (td, J=15.3, 9.8 Hz, 1H),2.79-2.99 (m, 1H). m/z (ESI, positive ion) 555.2 (M+H)⁺. Data for peak2: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 11.65 (s, 1H), 8.73 (d, J=1.7 Hz,1H), 8.37 (d, J=2.3 Hz, 1H), 8.23 (d, J=9.7 Hz, 1H), 7.84 (dd, J=8.9,2.3 Hz, 1H), 7.49 (d, J=10.0 Hz, 1H), 7.44 (d, J=6.2 Hz, 1H), 6.80 (d,J=9.7 Hz, 1H), 6.76 (d, J=9.1 Hz, 1H), 6.45 (d, J=1.7 Hz, 1H), 5.96-6.17(m, 2H), 5.85 (s, 1H), 3.70 (s, 3H), 3.14 (td, J=15.5, 9.6 Hz, 1H),2.79-2.99 (m, 1H). m/z (ESI, positive ion) 555.4 (M+H)⁺.

Examples 10 and 11:Cis-(P)-1-(5-Chloro-4-(3-Fluoro-3-(Trifluoromethyl)Cyclobutyl)-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-SulfonamideandTrans-(P)-1-(5-Chloro-4-(3-Fluoro-3-(Trifluoromethyl)Cyclobutyl)-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide,Respectively

Step 1:(P)-1-(5-Chloro-2-Methoxy-4-(3-Oxocyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A 3-neck 250-mL round-bottom flask equipped with reflux adapter andinternal temp probe was charged with(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(5 g, 7.93 mmol), palladium(II) acetate (0.107 g, 0.476 mmol), and2′-(dicyclohexylphosphino)-N²,N²,N⁶,N⁶-tetramethyl-[1,1′-biphenyl]-2,6-diamine(0.415 g, 0.951 mmol) then evacuated and backfilled with nitrogen.5,8-Dioxaspiro[3.4]octan-2-ylzinc(II) bromide (0.4 M in THF, 30 mL, 12mmol) was added, and the reaction was stirred at 50° C. for 20 h. Themixture was then quenched with 2 N aq. HCl (80 mL). The temperature waselevated to 50° C., and the mixture was stirred for 4 h. The mixture wasthen partitioned between water and EtOAc. The layers were separated. Theaqueous extract was extracted with EtAOc (2×100 mL). The combinedextracts were washed with brine and then concentrated to a blackresidue. The product was purified by column chromatography, (200 gsilica column, gradient elution 0-100% EtOAc:heptane) to afford(P)-1-(5-chloro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamideas a tan solid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.80 (d, J=1.6 Hz, 1H),8.36 (d, J=2.1 Hz, 1H), 8.15 (d, J=9.9 Hz, 1H), 7.78 (dd, J=9.1, 2.1 Hz,1H), 7.56 (s, 1H), 7.47 (s, 1H), 7.25 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.6Hz, 2H), 6.82 (d, J=9.6 Hz, 1H), 6.69-6.76 (m, 2H), 4.91 (s, 2H),3.97-4.07 (m, 2H), 3.75 (s, 3H), 3.71 (s, 3H), 3.47-3.52 (m, 3H). m/z(ESI, positive ion) 620.0 (M+H)⁺.

Step 2:(P)-1-(5-Chloro-4-(3-Hydroxy-3-(Trifluoromethyl)Cyclobutyl)-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A 25-mL round-bottom flask was charged with(P)-1-(5-chloro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.806 g, 1.30 mmol) and THF (6.5 mL) and equipped with an internal tempprobe. (Trifluoromethyl)trimethylsilane (0.38 mL, 2.6 mmol) wasintroduced and tetrabutylammonium fluoride, 1.0 m solution intetrahydrofuran (1.300 ml, 1.300 mmol) was added dropwise to thereaction mixture ensuring the internal temperature did not exceed 35° C.An exotherm and bubbling was observed. The reaction was stirred for 3 hand then diluted with sat. aq. NH₄Cl and extracted twice with ethylacetate. The combined organic layers were washed with brine, dried withsodium sulfate, filtered, and concentrated. The material was purifiedvia column chromatography (BIOTAGE® SNAP 100 g column, gradient elution0-100% EtOAc:heptane) to afford(P)-1-(5-chloro-4-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamideas an off-white solid. m/z (ESI, positive ion) 690.0 (M+H)⁺.

Step 3:(P)-1-(5-Chloro-4-(3-Fluoro-3-(Trifluoromethyl)Cyclobutyl)-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A 2-neck 50-mL round-bottom flask equipped with a reflux adapter waspurged with nitrogen then charged with triethylamine trihydrofluoride(1.4 mL, 8.7 mmol), triethylamine (0.61 mL, 4.4 mmol), anddichloromethane (9.7 mL) and cooled to 0° C.Difluoro(morpholino)sulfonium tetrafluoroborate (1.58 g, 6.52 mmol) anda solution of(P)-1-(5-chloro-4-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(1.00 g, 1.45 mmol) in dichloromethane (4.8 mL) were added successively,and the reaction was warmed to 50° C. and stirred for 16 h. The reactionwas then cooled to 0° C. and quenched carefully with saturated aqueoussodium bicarbonate solution and then extracted thrice with ethylacetate. The combined organic layers were dried with magnesium sulfate,filtered, and concentrated. The material was purified via columnchromatography (BIOTAGE® SNAP 50 g column, gradient elution 0-100%EtOAc:heptane) to afford(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(599 mg, 0.866 mmol, 60% yield) as a tan solid. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 8.81 (d, J=1.0 Hz, 1H), 8.32-8.44 (m, 1H), 8.16 (d, J=9.6Hz, 1H), 7.78 (dd, J=9.1, 2.1 Hz, 1H), 7.67 (d, J=4.2 Hz, 1H), 7.47 (d,J=6.2 Hz, 1H), 7.26 (d, J=8.6 Hz, 2H), 6.80-6.90 (m, 3H), 6.69-6.77 (m,2H), 5.97-6.16 (m, 2H), 5.88 (s, 1H), 4.92 (s, 2H), 3.76 (d, J=4.7 Hz,3H), 3.71 (s, 3H), 3.06 (tt, J=15.8, 10.8 Hz, 1H), 2.78-2.96 (m, 1H).m/z (ESI, positive ion) 692.2 (M+H)⁺.

STEP 4:CIS-(P)-1-(5-CHLORO-4-(3-Fluoro-3-(Trifluoromethyl)Cyclobutyl)-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-SulfonamideandTrans-(P)-1-(5-Chloro-4-(3-Fluoro-3-(Trifluoromethyl)Cyclobutyl)-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A 40-mL vial was charged with(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(599 mg, 0.866 mmol) dichloromethane (1.3 mL), and TFA (1.3 mL). Thevial was sealed and warmed to 50° C. and stirred for 16 h. The reactionwas then concentrated under reduced pressure and purified by silica gelcolumn chromatography (50 g column, gradient elution 0-75% [3:1EtOAc/EtOH]:heptane). Further purification was accomplished using aChiralpak IC, 2×25 cm column. The mobile phase was run under isocraticconditions; supercritical CO₂ with 30% methanol; flow rate: 80 mL/min.The first eluting peak was assignedcis-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.The second eluting peak was assignedtrans-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.Data for peak 1: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.66 (s, 1H), 8.73 (d,J=1.8 Hz, 1H), 8.37 (d, J=1.8 Hz, 1H), 8.22 (d, J=9.9 Hz, 1H), 7.84 (dd,J=8.8, 2.1 Hz, 1H), 7.66 (s, 1H), 7.46 (s, 1H), 6.80 (dd, J=9.2, 4.3 Hz,2H), 6.44 (d, J=1.6 Hz, 1H), 5.97-6.14 (m, 2H), 5.88 (s, 1H), 3.75 (s,3H), 3.06 (td, J=15.8, 9.9 Hz, 1H), 2.78-2.94 (m, 1H). m/z (ESI,positive ion) 572.0 (M+H)⁺. Data for peak 2: ¹H NMR (500 MHz, DMSO-d₆) δppm 11.66 (s, 1H), 8.73 (d, J=1.6 Hz, 1H), 8.38 (d, J=2.1 Hz, 1H), 8.23(d, J=9.6 Hz, 1H), 7.84 (dd, J=8.8, 2.1 Hz, 1H), 7.66 (s, 1H), 7.45 (s,1H), 6.80 (d, J=9.9 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 6.45 (d, J=1.6 Hz,1H), 6.00-6.18 (m, 2H), 5.89 (s, 1H), 3.74 (s, 3H), 3.05 (td, J=16.2,9.5 Hz, 1H), 2.79-2.94 (m, 1H). m/z (ESI, positive ion) 572.0 (M+H)⁺.

Examples 12 & 13:Cis-(P)-1-(5-Chloro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-SulfonamideandTrans-(P)-1-(5-Chloro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide,Respectively

Step 1:(P)—O-(3-(2-Chloro-4-(6-(N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)Sulfamoyl)-2-Oxoquinolin-1(2H)-Yl)-5-Methoxyphenyl)-1-(Trifluoromethyl)Cyclobutyl)O-Phenyl Carbonothioate

(P)-1-(5-Chloro-4-(3-hydroxy-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(1.00 g, 1.45 mmol) was dissolved in THF (7.25 ml) and cooled to 0° C.Sodium hydride (60% dispersion in mineral oil. 0.087 g, 2.2 mmol) wasadded, and the reaction was allowed to warm to room temperature over 30minutes. Phenyl chlorothionoformate (0.50 mL, 3.6 mmol) was added andthe reaction was stirred for 2 hours. Saturated aqueous sodiumbicarbonate solution was then introduced. The mixture was extractedthrice with ethyl acetate and the combined organic layers were driedwith magnesium sulfate, filtered, and concentrated. The material waspurified via column chromatography (BIOTAGE® SNAP 50 g column, gradientelution 0-100% EtOAc:heptane) to afford(P)—O-(3-(2-chloro-4-(6-(N-(isoxazol-3-yl)-N-(4-methoxybenzyl)sulfamoyl)-2-oxoquinolin-1(2H)-yl)-5-methoxyphenyl)-1-(trifluoromethyl)cyclobutyl)0-phenyl carbonothioate (896 mg, 1.08 mmol, 75% yield) as a light yellowsolid. ¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.71-8.87 (m, 1H), 8.37 (d, J=1.8Hz, 1H), 8.15 (d, J=9.6 Hz, 1H), 7.73-7.82 (m, 1H), 7.56 (s, 1H),7.44-7.55 (m, 2H), 7.29-7.42 (m, 3H), 7.25 (d, J=8.3 Hz, 3H), 6.86 (d,J=8.8 Hz, 2H), 6.82 (d, J=9.9 Hz, 1H), 6.65-6.77 (m, 2H), 4.91 (s, 2H),3.75-3.80 (m, 3H), 3.71 (s, 3H), 3.67 (br d, J=9.1 Hz, 1H), 3.53-3.62(m, 1H), 3.33-3.42 (m, 2H), 3.04-3.18 (m, 1H). m/z (ESI, positive ion)826.1 (M+H)⁺.

Step 2:(P)-1-(5-Chloro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A 40-mL vial was charged with(P)—O-(3-(2-chloro-4-(6-(N-(isoxazol-3-yl)-N-(4-methoxybenzyl)sulfamoyl)-2-oxoquinolin-1(2H)-yl)-5-methoxyphenyl)-1-(trifluoromethyl)cyclobutyl)0-phenyl carbonothioate (896 mg, 1.08 mmol), toluene (11 mL),tri-n-butyltin hydride (2.87 mL, 10.8 mmol) and azobisisobutyronitrile(178 mg, 1.08 mmol). The reaction mixture was degassed with nitrogen for20 minutes, then sealed and heated to 50° C. for 1 hour. The reactionwas then stirred at rt for 16 h. During this time, a white solid hadformed, which was isolated and washed with heptane to afford(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(596 mg, 0.884 mmol, 82% yield) as an off-white solid. m/z (ESI,positive ion) 674.2 (M+H)⁺.

Step 3:Cis-(P)-1-(5-Chloro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-SulfonamideandTrans-(P)-1-(5-Chloro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A 20 mL vial was charged with(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(596 mg, 0.884 mmol), dichloromethane (1.4 mL) and TFA (1.4 mL). Thevial was sealed and warmed to 50° C. for 16 h. The reaction was thencooled to RT and concentrated under reduced pressure. The residue waspurified by column chromatography (50 g silica gel column, gradientelution 0-75% [3:1 EtOAc/EtOH]:heptane). Further purification wasaccomplished using two sequential Chiralcel OJ-H, 2×25 cm columns. Themobile phase was run under isocratic conditions; supercritical CO₂ with15% methanol; flow rate: 80 mL/min. The first eluting peak was assignedcis-(P)-1-(5-chloro-2-methoxy-4-((1S,3S)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(305 mg). The second eluting peak was assignedtrans-(P)-1-(5-chloro-2-methoxy-4-((1S,3S)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(72 mg). Data for peak 1: ¹H NMR (500 MHz, DMSO-d₆) δ ppm 11.65 (s, 1H),8.73 (d, J=1.8 Hz, 1H), 8.36 (d, J=2.1 Hz, 1H), 8.21 (d, J=9.6 Hz, 1H),7.83 (dd, J=9.0, 2.2 Hz, 1H), 7.50 (s, 1H), 7.18 (s, 1H), 6.79 (d, J=9.6Hz, 2H), 6.44 (d, J=1.8 Hz, 1H), 3.79 (br t, J=9.2 Hz, 1H), 3.73 (s,3H), 3.27-3.34 (m, 1H), 2.61-2.71 (m, 2H), 2.26-2.43 (m, 2H). m/z (ESI,positive ion) 554.0 (M+H)⁺. Data for peak 2: ¹H NMR (500 MHz, DMSO-d₆) δppm 11.65 (br s, 1H), 8.72 (d, J=1.6 Hz, 1H), 8.35 (d, J=1.8 Hz, 1H),8.21 (d, J=9.6 Hz, 1H), 7.84 (dd, J=9.1, 2.1 Hz, 1H), 7.51 (s, 1H), 7.37(s, 1H), 6.78 (dd, J=9.3, 6.0 Hz, 2H), 6.44 (d, J=1.6 Hz, 1H), 4.00(quin, J=8.9 Hz, 1H), 3.76 (s, 3H), 3.22-3.28 (m, 1H), 2.93 (br d, J=3.6Hz, 1H), 2.66-2.75 (m, 1H), 2.59-2.63 (m, 2H). m/z (ESI, positive ion)554.0 (M+H)⁺.

Example 14:(P)-1-(4-Cyclobutyl-5-Fluoro-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

To a vial was added(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(146 mg, 0.238 mmol), palladium(II) acetate (2.7 mg, 0.012 mmol),2′-(dicyclohexylphosphino)-N²,N²,N⁶,N⁶-tetramethyl-[1,1′-biphenyl]-2,6-diamine(8.3 mg, 0.019 mmol), and cyclobutylzinc bromide (0.5 M in THF, 0.95 mL,0.47 mmol). The reaction mixture was flushed with nitrogen and stirredat 50° C. for 1 h. The mixture was then purified directly via columnchromatography (gradient elution 0-30% [3:1 EtOAc/EtOH]:heptane). Theisolated product was then taken up in TFA (0.5 mL) and heated to 50° C.for 16 h. The reaction was then concentrated in vacuo and purified usinga Torus 2-PIC, 30×150 cm column. The mobile phase was run under gradientelution conditions; supercritical CO₂ with 20-50% methanol; flow rate:100 mL/min. This afforded(P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(101 mg, 0.215 mmol, 90% yield). ¹H NMR (600 MHz, DMSO-d₆) δ ppm11.23-12.01 (m, 1H), 8.70 (d, J=1.5 Hz, 1H), 8.34 (d, J=2.2 Hz, 1H),8.19 (d, J=9.4 Hz, 1H), 7.83 (dd, J=9.1, 2.2 Hz, 1H), 7.24 (d, J=9.8 Hz,1H), 7.19 (d, J=6.9 Hz, 1H), 6.77 (d, J=9.4 Hz, 2H), 6.43 (d, J=1.8 Hz,1H), 3.74-3.83 (m, 1H), 3.69 (s, 3H), 2.32-2.40 (m, 3H), 2.22-2.31 (m,1H), 2.01-2.13 (m, 1H), 1.84-1.94 (m, 1H). m/z (ESI, positive ion) 470.0(M+H)⁺.

Example 15:Trans-(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-2-Oxo-N-(Pyrimidin-2-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

To a vial was added(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(359 mg, 0.573 mmol), palladium(II) acetate (6.4 mg, 0.029 mmol),2′-(dicyclohexylphosphino)-N²,N²,N⁶,N⁶-tetramethyl-[1,1′-biphenyl]-2,6-diamine(25 mg, 0.057 mmol), (3-(trifluoromethyl)cyclobutyl)zinc(II) bromide(0.15 M in THF, 5.7 mL, 0.86 mmol) was added. The reaction mixture wasflushed with nitrogen and stirred at 50° C. for 1 h. The mixture wasthen purified directly via column chromatography (gradient elution 0-30%[3:1 EtOAc/EtOH]:heptane). The isolated product was then taken up in TFA(0.5 mL) and heated to 50° C. for 16 h. The reaction was thenconcentrated in vacuo and purified using sequential Chiralcel OJ-H, 2+15and 2×25 cm columns. The mobile phase was run under isocraticconditions; supercritical CO₂ with 20% methanol; flow rate: 80 mL/min.This affordedtrans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(63 mg). ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.60-9.88 (m, 1H),8.51-8.63 (m, 2H), 8.44 (d, J=2.1 Hz, 1H), 8.06 (dd, J=9.0, 2.2 Hz, 1H),7.85 (d, J=9.9 Hz, 1H), 6.99 (t, J=4.9 Hz, 1H), 6.91-6.96 (m, 2H), 6.85(d, J=9.6 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 3.98 (quin, J=8.8 Hz, 1H),3.73 (s, 3H), 3.04 (dtd, J=14.9, 9.8, 9.8, 4.9 Hz, 1H), 2.67-2.79 (m,2H), 2.54-2.66 (m, 2H). m/z (ESI, positive ion) 549.2 (M+H)⁺.

Examples 16 & 17:Cis-(P)-1-(5-Chloro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-2-Oxo-N-(Pyrimidin-2-Yl)-1,2-Dihydroquinoline-6-SulfonamideandTrans-(P)-1-(5-Chloro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-2-Oxo-N-(Pyrimidin-2-Yl)-1,2-Dihydroquinoline-6-Sulfonamide,Respectively

The title compounds were prepared according to the method of Example 15using(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(368 mg, 0.573 mmol). The sample was purified using a Chiralcel OJ-H,2×15 cm column. The mobile phase was run under isocratic conditions;supercritical CO₂ with 30% methanol; flow rate: 80 mL/min. The samplewas further purified using a Chiralcel OJ-H, 3×25 cm column. The mobilephase was run under isocratic conditions; supercritical CO₂ with 20%methanol; flow rate: 100 mL/min. The first eluting peak was assignedcis-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(21.8 mg). The second eluting peak was assignedtrans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(142.8 mg). Data for peak 1: ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm9.99-10.35 (m, 1H), 8.59 (d, J=4.7 Hz, 2H), 8.43 (d, J=2.1 Hz, 1H), 8.07(dd, J=9.0, 2.2 Hz, 1H), 7.85 (d, J=9.6 Hz, 1H), 7.19 (s, 1H), 7.02 (s,1H), 6.99 (t, J=4.9 Hz, 1H), 6.85 (d, J=9.6 Hz, 1H), 6.76 (d, J=9.1 Hz,1H), 3.82 (quin, J=9.3 Hz, 1H), 3.76 (s, 3H), 2.99-3.11 (m, 1H),2.66-2.77 (m, 2H), 2.37 (quin, J=10.8 Hz, 2H). m/z (ESI, positive ion)564.8 (M+H)⁺. Data for peak 2: ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm9.09-9.31 (m, 1H), 8.54 (d, J=4.9 Hz, 2H), 8.44 (d, J=2.1 Hz, 1H), 8.07(dd, J=9.0, 2.2 Hz, 1H), 7.85 (d, J=9.6 Hz, 1H), 7.21 (s, 1H), 7.05 (s,1H), 6.98 (t, J=4.9 Hz, 1H), 6.85 (d, J=9.6 Hz, 1H), 6.76 (d, J=8.8 Hz,1H), 4.04-4.13 (m, 1H), 3.77 (s, 3H), 2.92-3.05 (m, 1H), 2.71-2.84 (m,2H), 2.47-2.66 (m, 2H). m/z (ESI, positive ion) 564.8 (M+H)⁺.

Example 18:(P)-1-(5-Chloro-4-Cyclobutyl-2-Methoxyphenyl)-2-Oxo-N-(Pyrimidin-2-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

The title compound was prepared according to the method of Example 14using(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(153 mg, 0.238 mmol). The sample was purified via reverse phase HPLCusing a XBridge Prep Shield RP18 19×100 mm column. The mobile was rununder a gradient elution; 25-70% acetonitrile:water with 0.1% formicacid; flow rate: 40 mL/min. This afforded(P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(18 mg, 0.036 mmol, 15% yield). ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm11.20-11.51 (m, 1H), 8.65 (d, J=4.9 Hz, 2H), 8.41 (d, J=2.1 Hz, 1H),8.04 (dd, J=9.1, 2.1 Hz, 1H), 7.84 (d, J=9.6 Hz, 1H), 7.15 (s, 1H), 7.06(s, 1H), 7.01 (t, J=5.1 Hz, 1H), 6.85 (d, J=9.9 Hz, 1H), 6.77 (d, J=8.8Hz, 1H), 3.87 (quin, J=8.8 Hz, 1H), 3.75 (s, 3H), 2.44-2.53 (m, 2H),2.15-2.30 (m, 2H), 2.03-2.15 (m, 1H), 1.85-1.97 (m, 1H). m/z (ESI,positive ion) 497.0 (M+H)⁺.

Example 19:Trans-(P)-1-(5-Chloro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-2-Oxo-N-(Pyridazin-3-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

The title compound was prepared according to the method of Example 15using(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide(368 mg, 0.573 mmol). The sample was purified using a Zorbax EclipsePlus C18, 2.1×10 cm column. The mobile phase was run under gradientelution conditions; 41.3-61.3% water:acetonitrile with 0.1% formic acidas co-eluent; flow rate: 40 mL/min. The material was further purifiedusing a Chiralcel OJ-H, 2×15 cm column. The mobile phase was run underisocratic conditions; supercritical CO₂ with 25% methanol; flow rate: 80mL/min. This affordedtrans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide(38.4 mg). ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 12.38-12.76 (m, 1H),8.24 (d, J=2.1 Hz, 1H), 8.10 (dd, J=3.9, 1.6 Hz, 1H), 7.91 (dd, J=9.1,2.1 Hz, 1H), 7.83 (d, J=9.6 Hz, 1H), 7.33-7.37 (m, 1H), 7.29 (d, J=1.6Hz, 1H), 7.21 (s, 1H), 7.05 (s, 1H), 6.84 (d, J=9.6 Hz, 1H), 6.75 (d,J=8.8 Hz, 1H), 4.08 (quin, J=8.9 Hz, 1H), 3.77 (s, 3H), 2.91-3.06 (m,1H), 2.69-2.83 (m, 2H), 2.48-2.62 (m, 2H). m/z (ESI, positive ion) 565.2(M+H)⁺.

Example 20:Trans-(P)—N-(Isoxazol-3-Yl)-1-(2-Methoxy-5-Methyl-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

The title compound was prepared according to the method of Example 15using(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(350 mg, 0.573 mmol). The sample was purified using a Zorbax EclipsePlus C18, 2.1×10 cm column. The mobile phase was run under gradientelution conditions; 46.4-66.4% acetonitrile:water with 0.1% formic acidas co-eluent; flow rate: 40 mL/min. The material was further purifiedusing a Chiralcel OJ-H, 2×15 cm column. The mobile phase was run underisocratic conditions; supercritical CO₂ with 20% methanol; flow rate: 80mL/min. This affordedtrans-(P)—N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(65.8 mg). ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.25 (d, J=1.8 Hz, 1H),8.11 (d, J=2.1 Hz, 1H), 7.83-8.04 (m, 1H), 7.76 (d, J=9.6 Hz, 1H), 7.72(dd, J=9.0, 2.2 Hz, 1H), 7.01 (s, 1H), 6.95 (s, 1H), 6.86 (d, J=9.6 Hz,1H), 6.76 (d, J=9.1 Hz, 1H), 6.60 (d, J=1.8 Hz, 1H), 3.94 (quin, J=8.8Hz, 1H), 3.75 (s, 3H), 2.89-3.07 (m, 1H), 2.70 (ddd, J=12.8, 8.8, 4.0Hz, 2H), 2.46-2.60 (m, 2H), 2.19 (s, 3H). m/z (ESI, positive ion) 534.2(M+H)⁺.

Example 21:(P)-1-(5-Chloro-4-Cyclobutyl-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

The title compound was prepared according to the method of Example 14using(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(150 mg, 0.238 mmol). The sample was purified via reverse phase HPLCusing a XBridge Prep Shield RP18 19×100 mm column. The mobile was rununder a gradient elution; 25-70% acetonitrile:water with 0.1% formicacid; flow rate: 40 mL/min. This afforded(P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(92 mg, 80% yield). ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.40 (br s,1H), 8.25 (d, J=1.6 Hz, 1H), 8.13 (d, J=2.1 Hz, 1H), 7.78 (d, J=9.6 Hz,1H), 7.75 (dd, J=9.0, 2.2 Hz, 1H), 7.15 (s, 1H), 7.05 (s, 1H), 6.87 (d,J=9.6 Hz, 1H), 6.77 (d, J=9.1 Hz, 1H), 6.59 (d, J=1.8 Hz, 1H), 3.80-3.91(m, 1H), 3.75 (s, 3H), 2.42-2.56 (m, 2H), 2.16-2.27 (m, 2H), 2.04-2.16(m, 1H), 1.84-1.96 (m, 1H). m/z (ESI, positive ion) 486.0 (M+H)⁺.

Example 22:(P)-1-(4-Cyclobutyl-2-Methoxy-5-Methylphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-DihydroQuinoline-6-Sulfonamide

Step 1:(P)-1-(4-Cyclobutyl-2-Methoxy-5-Methylphenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

To a THF (1 mL) solution of(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(191 mg, 0.313 mmol) was added2-dicyclohexylphosphino-2′,6′-dimethylamino-1,1′-biphenyl (27.3 mg,0.063 mmol), and palladium(II) acetate (14.05 mg, 0.063 mmol). Thereaction mixture was sparged with argon, and then cyclobutylzinc bromide(0.5 M in THF, 1.9 mL, 0.94 mmol) was added. The reaction was stirred at50° C. After 2 h, additional portions of2-dicyclohexylphosphino-2′,6′-dimethylamino-1,1′-biphenyl (27.3 mg,0.063 mmol), palladium(II) acetate (14.1 mg, 0.063 mmol), andcyclobutylzinc bromide (0.5 M in THF, 1.9 mL, 0.94 mmol) were added.After stirring for 1 h at 50° C., the reaction was cooled to roomtemperature, quenched with saturated aqueous sodium bicarbonate, andpartitioned between water and ethyl acetate. The organic extract wasconcentrated and purified by silica gel column chromatography (gradientelution, 40-100% EtOAc:heptane with 10% dichloromethane co-eluent) toafford(P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(123 mg, 0.210 mmol, 67% yield) as a brown solid. m/z (ESI, positiveion) 586.0 (M+H)⁺.

Step 2:(P)-1-(4-Cyclobutyl-2-Methoxy-5-Methylphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

(P)-1-(4-Cyclobutyl-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(123 mg, 0.210 mmol) was dissolved in TFA (2 mL) and stirred at 40° C.After 2 h, the reaction was concentrated, and the residue was purifiedvia silica gel column chromatography (gradient elution 20-80% [3:1EtOAc/EtOH]:heptane with 10% dichloromethane co-eluent) to afford(P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(73 mg, 0.157 mmol, 75% yield) as a light purple solid. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 11.60 (br s, 1H), 8.71 (d, J=1.8 Hz, 1H), 8.33 (d, J=2.1Hz, 1H), 8.18 (d, J=9.6 Hz, 1H), 7.82 (dd, 2.2 Hz, 1H), 7.09 (s, 1H),7.00 (s, 1H), 6.77 (d, J=9.6 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 6.43 (d,J=1.8 Hz, 1H), 3.69-3.74 (m, 1H), 3.68 (s, 3H), 2.33-2.43 (m, 2H), 2.26(quin, J=9.6 Hz, 1H), 2.11-2.19 (m, 4H), 1.98-2.09 (m, 1H), 1.79-1.90(m, 1H). m/z (ESI, positive ion) 465.8 (M+H)⁺.

Example 23:(P)-1-(4-Cyclobutyl-5-Fluoro-2-Methoxyphenyl)-2-Oxo-N-(Pyridazin-3-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

Step 1:(P)-1-(4-Cyclobutyl-5-Fluoro-2-Methoxyphenyl)-N-(4-Methoxybenzyl)-2-Oxo-N-(Pyridazin-3-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

To a THF (0.8 mL) solution of a(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide(150 mg, 0.240 mmol) was added2-dicyclohexylphosphino-2′,6′-dimethylamino-1,1′-biphenyl (20.9 mg,0.048 mmol), and palladium(II) acetate (10.8 mg, 0.048 mmol). Thereaction mixture was sparged with argon, and then cyclobutylzinc bromide(0.5m in THF, 1.4 mL, 0.72 mmol) was added. The reaction was stirred at50° C. After 90 min, the reaction mixture was quenched with saturatedaqueous sodium bicarbonate and partitioned between water and ethylacetate. The organic layers were concentrated. The residue was purifiedby silica gel column chromatography (gradient elution 40-100%EtOAc:heptane with 10% dichloromethane co-eluent) to afford(P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide(156 mg, 0.260 mmol, >99% yield) as a brown solid. m/z (ESI, positiveion) 601.0 (M+H)⁺.

Step 2:(P)-1-(4-Cyclobutyl-5-Fluoro-2-Methoxyphenyl)-2-Oxo-N-(Pyridazin-3-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

(P)-1-(4-Cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide(156 mg, 0.260 mmol) was dissolved in TFA (3.0 mL) and stirred at 40° C.After 2 h, the reaction was concentrated, and the residue was purifiedby silica gel chromatography 20-80% [3:1 EtOAc/EtOH]:heptane with 10%dichloromethane co-eluent) to afford1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide(86 mg, 0.179 mmol, 69% yield) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 14.28-14.68 (m, 1H), 8.23-8.39 (m, 2H), 8.17 (d, J=9.6Hz, 1H), 7.89-8.00 (m, 1H), 7.79-7.86 (m, 1H), 7.68 (dd, J=9.5, 4.0 Hz,1H), 7.22 (d, J=9.9 Hz, 1H), 7.19 (d, J=6.7 Hz, 1H), 6.75 (d, J=9.6 Hz,1H), 6.70 (d, J=8.8 Hz, 1H), 3.78 (quin, J=8.9 Hz, 1H), 3.69 (s, 3H),2.32-2.38 (m, 3H), 2.23-2.32 (m, 1H), 2.02-2.14 (m, 1H), 1.84-1.95 (m,1H). m/z (ESI, positive ion) 480.8 (M+H)⁺.

Example 24:(P)-1-(4-Cyclobutyl-5-Fluoro-2-Methoxyphenyl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

The title compound was prepared according to the method and purificationprotocol of Example 23 using(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(180 mg, 0.293 mmol). This afforded(P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(54 mg, 0.115 mmol, 39% yield over 2 steps) as a light purple solid. ¹HNMR (500 MHz, CHLOROFORM-d) δ ppm 9.65-10.09 (m, 1H), 8.19 (d, J=2.1 Hz,1H), 7.87 (dd, 2.2 Hz, 1H), 7.81 (d, J=9.6 Hz, 1H), 7.08 (d, J=1.8 Hz,1H), 6.98 (d, J=6.2 Hz, 1H), 6.88 (d, J=9.3 Hz, 1H), 6.86 (d, J=1.8 Hz,1H), 6.84 (d, J=9.6 Hz, 1H), 6.76 (d, J=9.1 Hz, 1H), 3.82 (quin, J=8.8Hz, 1H), 3.72 (s, 3H), 2.39-2.49 (m, 2H), 2.21-2.34 (m, 2H), 2.08-2.18(m, 1H), 1.88-1.99 (m, 1H). m/z (ESI, positive ion) 469.8 (M+H)⁺.

Example 25:(P)-1-(4-Cyclobutyl-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

The title compound was prepared according to the method and purificationprotocol of Example 23 using(P)-1-(4-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(140 mg, 0.235 mmol). This afforded(P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(89 mg, 0.197 mmol, 84% yield over 2 steps) as an off-white solid. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 11.60 (s, 1H), 8.72 (d, J=1.8 Hz, 1H), 8.34(d, J=2.3 Hz, 1H), 8.19 (d, J=9.9 Hz, 1H), 7.83 (dd, J=9.0, 2.2 Hz, 1H),7.18 (d, J=8.0 Hz, 1H), 7.12 (d, J=1.6 Hz, 1H), 7.02 (dd, J=7.9, 1.7 Hz,1H), 6.77 (d, J=9.6 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 6.44 (d, J=1.8 Hz,1H), 3.67 (s, 3H), 3.58-3.67 (m, 1H), 2.32-2.42 (m, 2H), 2.16-2.27 (m,2H), 1.99-2.08 (m, 1H), 1.82-1.92 (m, 1H). m/z (ESI, positive ion) 452.0(M+H)⁺.

Example 26:(P)-1-(4-Cyclobutyl-2-Methoxyphenyl)-2-Oxo-N-(Pyrimidin-2-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

The title compound was prepared according to the method and purificationprotocol of Example 23 using(P)-1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(140 mg, 0.230 mmol). This afforded(P)-1-(4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(50 mg, 0.108 mmol, 47% yield over 2 steps) as a white solid. ¹H NMR(500 MHz, CHLOROFORM-d) δ ppm 8.57 (d, J=4.9 Hz, 2H), 8.42 (d, J=2.1 Hz,1H), 8.02 (dd, J=9.1, 2.1 Hz, 1H), 7.84 (d, J=9.6 Hz, 1H), 7.07-7.10 (m,1H), 6.93-7.03 (m, 3H), 6.87 (d, J=9.6 Hz, 1H), 6.78 (d, J=9.1 Hz, 1H),3.72 (s, 3H), 3.65 (quin, J=9.0 Hz, 1H), 2.34-2.46 (m, 2H), 2.18-2.31(m, 2H), 2.06-2.14 (m, 1H), 1.85-1.96 (m, 1H). m/z (ESI, positive ion)463.0 (M+H)⁺.

Example 27:(P)-1-(4-Cyclobutyl-2-Methoxy-5-Methylphenyl)-2-Oxo-N-(Pyrimidin-2-Yl)-1,2-DihydroQuinoline-6-Sulfonamide

The title compound was prepared according to the method and purificationprotocol of Example 22 using(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(130 mg, 0.209 mmol). This afforded(P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(60 mg, 0.126 mmol, 60% yield over 2 steps) as a white solid. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 11.43-12.18 (m, 1H), 8.50 (d, J=4.9 Hz, 2H),8.44 (d, J=2.1 Hz, 1H), 8.21 (d, J=9.6 Hz, 1H), 7.95 (dd, J=9.0, 2.2 Hz,1H), 7.09 (s, 1H), 7.05 (br t, J=4.8 Hz, 1H), 6.99 (s, 1H), 6.75 (d,J=9.9 Hz, 1H), 6.69 (d, J=9.1 Hz, 1H), 3.68-3.75 (m, 1H), 3.67 (s, 3H),2.32-2.44 (m, 2H), 2.26 (quin, J=9.7 Hz, 1H), 2.11-2.20 (m, 4H),1.99-2.07 (m, 1H), 1.80-1.90 (m, 1H). m/z (ESI, positive ion) 477.0(M+H)⁺.

Example 28:(P)-1-(4-CYCLOBUTYL-5-FLUORO-2-METHOXYPHENYL)-2-Oxo-N-(Pyrimidin-2-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

The title compound was prepared according to the method and purificationprotocol of Example 23 using(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(120 mg, 0.192 mmol). This afforded(P)-1-(4-cyclobutyl-5-fluoro-2-methoxyphenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(20 mg, 0.042 mmol, 22% yield). ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm8.59 (d, J=4.9 Hz, 2H), 8.43 (d, J=2.1 Hz, 1H), 8.06 (dd, J=9.0, 2.2 Hz,1H), 7.84 (d, J=9.6 Hz, 1H), 6.96-7.02 (m, 2H), 6.87 (d, J=3.6 Hz, 1H),6.85 (d, J=4.4 Hz, 1H), 6.78 (d, J=9.1 Hz, 1H), 3.82 (quin, J=9.1 Hz,1H), 3.72 (s, 3H), 2.37-2.48 (m, 2H), 2.23-2.35 (m, 2H), 2.07-2.18 (m,1H), 1.88-2.00 (m, 1H). m/z (ESI, positive ion) 481.0 (M+H)⁺.

Example 29:(P)-1-(4-Cyclobutyl-2-Methoxyphenyl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

Step 1:(P)-1-(4-Cyclobutyl-2-Methoxyphenyl)-N-(2,4-Dimethoxybenzyl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

To a THF (1.2 mL) solution of(P)-1-(4-bromo-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(200 mg, 0.319 mmol) was added2-dicyclohexylphosphino-2′,6′-dimethylamino-1,1′-biphenyl (41.8 mg,0.096 mmol) and palladium(II) acetate (21.50 mg, 0.096 mmol). Thereaction mixture was sparged with argon, and then cyclobutylzinc bromide(0.5 M in THF, 2.55 mL, 1.28 mmol) was added. The reaction was stirredat 50° C. After 3 h, the reaction was quenched with saturated aqueoussodium bicarbonate and partitioned between water and ethyl acetate. Theorganic layer was concentrated. The residue were purified by silica gelcolumn chromatography (gradient elution 40-100% ethyl acetate:heptanewith 10% dichloromethane as a co-eluent) to provide(P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(73 mg, 0.12 mmol, 38% yield) as a yellow oil. m/z (ESI, positive ion)602.0 (M+H)⁺.

Step 2:(P)-1-(4-Cyclobutyl-2-Methoxyphenyl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

(P)-1-(4-Cyclobutyl-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(73 mg, 0.12 mmol) was dissolved in TFA (3.0 mL). The reaction mixturewas stirred at 40° C. After 1 h, the reaction was concentrated, and theresidue was purified by silica gel column chromatography (gradientelution 20-80% [3:1 EtOAc/EtOH]:heptane with 10% dichloromethaneco-eluent) to afford(P)-1-(4-cyclobutyl-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(46 mg, 0.10 mmol, 85% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 12.12 (br s, 1H), 8.29 (d, J=2.1 Hz, 1H), 8.15 (d, J=9.6Hz, 1H), 7.83 (dd, J=9.0, 2.2 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.26 (d,J=1.6 Hz, 1H), 7.17 (d, J=7.8 Hz, 1H), 7.12 (d, J=1.6 Hz, 1H), 7.02 (dd,J=8.0, 1.6 Hz, 1H), 6.74 (d, J=9.6 Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 3.68(s, 3H), 3.58-3.67 (m, 1H), 2.31-2.39 (m, 2H), 2.17-2.28 (m, 2H),1.96-2.10 (m, 1H), 1.82-1.92 (m, 1H). m/z (ESI, positive ion) 451.8(M+H)⁺.

Example 30:(P)-1-(4-Cyclobutyl-2-Methoxy-5-Methylphenyl)-2-Oxo-N-(Pyridazin-3-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

The title compound was prepared according to the method and purificationprotocol of Example 23 using(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide(367 mg, 0.591 mmol). This afforded(P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide(144 mg, 0.302 mmol, 51% yield over 2 steps) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 14.35-14.59 (m, 1H), 8.23-8.34 (m, 2H), 8.16(d, J=9.5 Hz, 1H), 7.88-7.98 (m, 1H), 7.82 (br d, J=8.3 Hz, 1H),7.59-7.73 (m, 1H), 7.08 (s, 1H), 6.99 (s, 1H), 6.74 (d, J=9.5 Hz, 1H),6.65 (d, J=8.9 Hz, 1H), 3.63-3.76 (m, 4H), 2.31-2.44 (m, 2H), 2.21-2.30(m, 1H), 2.13-2.20 (m, 4H), 2.00-2.09 (m, 1H), 1.81-1.92 (m, 1H). m/z(ESI, positive ion) 477.0 (M+H)⁺.

Example 31:(P)-1-(4-Cyclobutyl-2-Methoxyphenyl)-2-Oxo-N-(Pyridazin-3-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

The title compound was prepared according to the method of Example 23using(P)-1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide(300 mg, 0.494 mmol). The sample was purified via reverse phase HPLCusing a XBridge Prep Shield RP18 19×100 mm column. The mobile was rununder a gradient elution; 15-70% acetonitrile:water with 0.1% formicacid; flow rate: 40 mL/min. This afforded(P)-1-(4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide(130 mg, 0.281 mmol, 57% yield over 2 steps) as a white solid. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 14.39 (br s, 1H), 8.31 (d, J=2.1 Hz, 2H), 8.16(d, J=9.6 Hz, 1H), 7.85-7.93 (m, 1H), 7.82 (dd, J=9.0, 2.2 Hz, 1H), 7.66(dd, J=9.6, 4.2 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.11 (d, J=1.6 Hz, 1H),7.02 (dd, J=8.0, 1.3 Hz, 1H), 6.74 (d, J=9.6 Hz, 1H), 6.64 (d, J=8.8 Hz,1H), 3.67 (s, 3H), 3.59-3.66 (m, 1H), 2.30-2.41 (m, 2H), 2.16-2.29 (m,2H), 1.96-2.10 (m, 1H), 1.81-1.93 (m, 1H). m/z (ESI, positive ion) 463.0(M+H)⁺.

Example 32:(P)-1-(5-Chloro-4-Cyclobutyl-2-Methoxyphenyl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

The title compound was prepared according to the method of Example 23using(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(347 mg, 0.525 mmol). The sample was purified via reverse phase HPLCusing a XBridge Prep Shield RP18 19×100 mm column. The mobile was rununder a gradient elution; 15-60% acetonitrile:water with 0.1% formicacid; flow rate: 40 mL/min. The material was further purified using aWhelk-O, 2×15 cm column. The mobile phase was run under isocraticconditions; supercritical CO₂ with 60% isopropanol; flow rate: 70mL/min. This afforded(P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(74 mg, 0.15 mmol, 29% yield over 2 steps) as a white solid. ¹H NMR (500MHz, DMSO-d₆) δ ppm 12.15 (br s, 1H), 8.30 (d, J=2.1 Hz, 1H), 8.16 (d,J=9.6 Hz, 1H), 7.84 (dd, J=9.0, 2.2 Hz, 1H), 7.59 (d, J=1.6 Hz, 1H),7.43 (s, 1H), 7.23-7.30 (m, 2H), 6.75 (d, J=9.6 Hz, 1H), 6.69 (d, J=8.8Hz, 1H), 3.82 (quin, J=8.8 Hz, 1H), 3.74 (s, 3H), 2.39-2.44 (m, 2H),2.29-2.35 (m, 1H), 2.23 (quin, J=9.5 Hz, 1H), 2.00-2.12 (m, 1H),1.81-1.92 (m, 1H). m/z (ESI, positive ion) 486.0 (M+H)⁺.

Example 33:(P)-1-(5-Chloro-4-Cyclobutyl-2-Methoxyphenyl)-2-Oxo-N-(Pyridazin-3-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

Step 1:(P)-1-(5-Chloro-4-Cyclobutyl-2-Methoxyphenyl)-N-(4-Methoxybenzyl)-2-Oxo-N-(Pyridazin-3-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

To a 20-mL scintillation vial was added2-dicyclohexylphosphino-2′,6′-dimethylamino-1,1′-biphenyl (20.4 mg,0.047 mmol), palladium(II) acetate (5.3 mg, 0.023 mmol), and(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide(300 mg, 0.467 mmol). The reaction mixture was sparged with nitrogen,and then cyclobutylzinc bromide (0.5 M in THF, 1.87 mL, 0.935 mmol) wasadded. After stirring at 50° C. for 1 h, an additional portion ofcyclobutylzinc bromide (0.5 M in THF, 1.87 mL, 0.935 mmol) was added.After stirring an additional 2 h at 50° C., the reaction mixture wasquenched with saturated aqueous sodium bicarbonate and partitionedbetween water and ethyl acetate. The organic layer was concentrated. Theinitial products were purified by silica gel column chromatography(gradient elution 0-60% [3:1 EtOAc/EtOH]:heptane with 10%dichloromethane co-eluent) to provide(P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide(216 mg, 0.350 mmol, 75% yield) as a yellow solid. m/z (ESI, positiveion) 616.8 (M+H)⁺.

Step 2:(P)-1-(5-Chloro-4-Cyclobutyl-2-Methoxyphenyl)-2-Oxo-N-(Pyridazin-3-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

(P)-1-(5-Chloro-4-cyclobutyl-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide(216 mg, 0.350 mmol) was taken up in trifluoroacetic acid (2.6 mL) andthe reaction was heated to 40° C. After 2 h, the reaction was thenconcentrated and purified via reverse phase HPLC using a XBridge PrepShield RP18 19×100 mm column. The mobile was run under a gradientelution; 15-70% acetonitrile:water with 0.1% formic acid; flow rate: 40mL/min. This afforded(P)-1-(5-chloro-4-cyclobutyl-2-methoxyphenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide(83 mg, 0.167 mmol, 48% yield) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆) δ ppm 14.46 (br s, 1H), 8.33 (d, J=2.1 Hz, 2H), 8.17 (d, J=9.6Hz, 1H), 7.88 (br d, J=3.9 Hz, 1H), 7.83 (dd, J=9.0, 2.2 Hz, 1H), 7.67(dd, J=9.6, 4.2 Hz, 1H), 7.42 (s, 1H), 7.24 (s, 1H), 6.75 (d, J=9.6 Hz,1H), 6.69 (d, J=8.8 Hz, 1H), 3.82 (quin, J=8.8 Hz, 1H), 3.73 (s, 3H),2.35-2.47 (m, 2H), 2.28-2.34 (m, 1H), 2.22 (quin, J=9.9 Hz, 1H),1.97-2.11 (m, 1H), 1.80-1.91 (m, 1H). m/z (ESI, positive ion) 497.0(M+H)⁺.

Example 34:(P)-1-(4-Cyclobutyl-2-Methoxy-5-Methylphenyl)-N-(2,4-Dimethoxybenzyl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

Step 1:(P)-1-(4-Cyclobutyl-2-Methoxy-5-Methylphenyl)-N-(2,4-Dimethoxybenzyl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

To a 20-mL scintillation vial was added2-dicyclohexylphosphino-2′,6′-dimethylamino-1,1′-biphenyl (26 mg, 0.060mmol), palladium(II) acetate (6.7 mg, 0.030 mmol), and(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(384 mg, 0.600 mmol). The reaction mixture was sparged with nitrogen,and then cyclobutylzinc bromide (0.5 M in tetrahydrofuran, 3.60 mL, 1.80mmol) was added. The reactions were stirred at 50° C. After 1 h, thereaction mixture was quenched with saturated aqueous sodium bicarbonateand partitioned between water and ethyl acetate. The organic layer wasdried over sodium sulfate and concentrated. The residue was purified bysilica gel column chromatography (gradient elution 0-30% [3:1EtOAc/EtOH]:heptane with 10% dichloromethane co-eluent) to provide(P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(255 mg, 0.414 mmol, 69% yield) as a white solid. m/z (ESI, positiveion) 616.2 (M+H)⁺.

Step 2:(P)-1-(4-Cyclobutyl-2-Methoxy-5-Methylphenyl)-N-(2,4-Dimethoxybenzyl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

(P)-1-(4-Cyclobutyl-2-methoxy-5-methylphenyl)-N-(2,4-dimethoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(255 mg, 0.414 mmol) was taken up in TFA (3 mL) and heated to 50° C.After stirring for 1 h, the reaction was concentrated and purified usinga Torus 2-PIC, 3×15 cm column. The mobile phase was run under gradientelution conditions; supercritical CO₂ with 10-40% methanol; flow rate:100 mL/min. This afforded(P)-1-(4-cyclobutyl-2-methoxy-5-methylphenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(71 mg, 0.15 mmol, 25% yield over 2 steps). ¹H NMR (600 MHz, DMSO-d₆) δppm 12.12 (br s, 1H), 8.29 (d, J=1.8 Hz, 1H), 8.15 (d, J=9.4 Hz, 1H),7.83 (dd, J=8.9, 2.0 Hz, 1H), 7.59 (d, J=1.5 Hz, 1H), 7.26 (d, J=1.5 Hz,1H), 7.09 (s, 1H), 6.99 (s, 1H), 6.74 (d, J=9.4 Hz, 1H), 6.65 (d, J=8.7Hz, 1H), 3.63-3.75 (m, 4H), 2.33-2.44 (m, 2H), 2.27 (quin, J=9.7 Hz,1H), 2.12-2.21 (m, 4H), 1.97-2.10 (m, 1H), 1.80-1.92 (m, 1H). m/z (ESI,positive ion) 466.0 (M+H)⁺.

Example 35:Trans-(P)—N-(Isoxazol-3-Yl)-1-(2-Methoxy-4-((Trifluoromethyl)Cyclobutyl)Phenyl)-2-Oxo-1,2-DihydroQuinoline-6-Sulfonamide

Step 1:(P)—N-(Isoxazol-3-Yl)-1-(2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

(P)-1-(4-Bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.47 g, 0.788 mmol), palladium(II) acetate (0.023 g, 0.10 mmol), and2-dicyclohexylphosphino-2′,6′-dimethylamino-1,1′-biphenyl (0.076 g,0.173 mmol) were placed in a vial, and the resulting mixture was spargedwith nitrogen prior to the addition of tetrahydrofuran (3.1 mL).(3-(Trifluoromethyl)cyclobutyl)zinc(II) bromide (0.125 M in THF, 9.46mL, 1.182 mmol) was then added dropwise. The reaction mixture was thenwarmed to 50° C. and stirred at this temperature for 1.25 h. Aftercooling to ambient temperature, the reaction mixture was quenched with 5M aqueous ammonium chloride solution, and the aqueous phase wasextracted twice with ethyl acetate. The combined organic extracts weredried over magnesium sulfate, filtered, and concentrated under vacuum.The resulting residue was purified by flash column chromatography(gradient elution 0-50% [3:1 EtOAc/EtOH]:heptane with 10%dichloromethane co-eluent) to afford(P)—N-(isoxazol-3-yl)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.489 g, 0.764 mmol, 97% yield). m/z (ESI, positive ion) 640.2 (M+H)⁺.

Step 2:Trans-(P)—N-(Isoxazol-3-Yl)-1-(2-Methoxy-4-((Trifluoromethyl)Cyclobutyl)Phenyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

(P)—N-(Isoxazol-3-yl)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.489 g, 0.764 mmol) was dissolved in TFA (1.3 mL) and stirred at 40°C. for 2.5 h. After cooling to ambient temperature, volatiles wereremoved under vacuum, and the residue was purified using aChromegaChiral CC4, 2×25 cm column. The mobile phase was run underisocratic conditions; supercritical CO₂ with 40% methanol; flow rate: 80mL/min. This affordedtrans-(P)—N-(isoxazol-3-yl)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(296 mg, 0.570 mmol, 72% yield over 2 steps). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 11.60 (s, 1H), 8.71 (d, J=1.6 Hz, 1H), 8.34 (d, J=2.1 Hz, 1H),8.19 (d, J=9.6 Hz, 1H), 7.83 (dd, J=9.1, 2.3 Hz, 1H), 7.20-7.28 (m, 2H),7.11 (dd, J=7.9, 1.4 Hz, 1H), 6.78 (d, J=9.6 Hz, 1H), 6.71 (d, J=9.1 Hz,1H), 6.43 (d, J=1.8 Hz, 1H), 3.80 (quin, J=8.6 Hz, 1H), 3.69 (s, 3H),3.22-3.28 (m, 1H), 2.54-2.61 (m, 4H). m/z (ESI, positive ion) 520.0(M+H)⁺.

Example 36:Trans-(P)-1-(2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-2-Oxo-N-(Pyrimidin-2-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

The title compound was prepared according to the method of Example 23 byusing(P)-1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(479 mg, 0.788 mmol) in place of(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide.The sample was purified using a Chiralpak IC, 2×15 cm column. The mobilephase was run under isocratic conditions; supercritical CO₂ with 60%[1:1 methanol:dichloromethane]; flow rate: 80 mL/min. This affordedtrans-(P)-1-(2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(204 mg, 0.384 mmol, 49% yield over 2 steps). ¹H NMR (500 MHz, DMSO-d₆)δ ppm 11.57-12.03 (m, 1H), 8.50 (br d, J=4.9 Hz, 2H), 8.45 (d, J=1.8 Hz,1H), 8.22 (d, J=9.6 Hz, 1H), 7.82-8.03 (m, 1H), 7.18-7.25 (m, 2H), 7.11(dd, J=8.0, 1.6 Hz, 1H), 7.05 (br s, 1H), 6.76 (d, J=9.6 Hz, 1H), 6.69(d, J=8.8 Hz, 1H), 3.80 (quin, J=9.0 Hz, 1H), 3.68 (s, 3H), 3.21-3.28(m, 1H), 2.53-2.63 (m, 4H). m/z (ESI, positive ion) 531.0 (M+H)⁺.

Example 37:Trans-(P)-1-(2-Methoxy-5-Methyl-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-2-Oxo-N-(Pyrimidin-2-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

The title compound was prepared according to the method of Example 35 byusing(P)-1-(4-bromo-2-methoxy-5-methylphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(470 mg, 0.756 mmol) in place of(P)-1-(4-Bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.The sample was purified using two sequential Chiralpak OJ-H, 3×15 cmcolumns. The mobile phase was run under isocratic conditions;supercritical CO₂ with 20% methanol; flow rate: 80 mL/min. The samplewas further purified via silica gel column chromatography (gradientelution 0-100% EtOAc:heptane with 10% dichloromethane co-eluent) toaffordtrans-(P)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(103 mg, 0.189 mmol, 25% yield over 2 steps) as a light pink solid. ¹HNMR (500 MHz, DMSO-d₆) δ ppm 14.17-14.75 (m, 1H), 8.25-8.35 (m, 2H),8.16 (d, J=9.9 Hz, 1H), 7.86-7.99 (m, 1H), 7.83 (dd, J=8.7, 1.7 Hz, 1H),7.67 (br dd, J=8.6, 3.9 Hz, 1H), 7.22 (s, 1H), 7.04 (s, 1H), 6.74 (d,J=9.6 Hz, 1H), 6.65 (d, J=9.1 Hz, 1H), 3.88 (quin, J=8.9 Hz, 1H), 3.71(s, 3H), 3.18-3.28 (m, 1H), 2.54-2.66 (m, 4H), 2.16 (s, 3H). m/z (ESI,positive ion) 545.0 (M+H)⁺.

Example 38:Trans-(P)-1-(2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-2-Oxo-N-(Pyridazin-3-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

The title compound was prepared according to the method of Example 35 byusing(P)-1-(4-bromo-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide(459 mg, 0.756 mmol) in place of(P)-1-(4-Bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.The sample was purified using a Chiralpak AS-H, 2×25 cm column. Themobile phase was run under isocratic conditions; supercritical CO₂ with35% methanol; flow rate: 50 mL/min. The sample was further purified viasilica gel column chromatography (gradient elution 0-100% EtOAc:heptanewith 10% dichloromethane co-eluent) to affordtrans-(P)-1-(2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide(247 mg, 466 mmol, 62% yield over 2 steps) as a light pink solid. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 14.26-14.69 (m, 1H), 8.23-8.35 (m, 2H), 8.16(d, J=9.6 Hz, 1H), 7.89-7.98 (m, 1H), 7.82 (br d, J=8.0 Hz, 1H), 7.68(br dd, J=9.7, 4.0 Hz, 1H), 7.18-7.25 (m, 2H), 7.11 (dd, J=8.0, 1.6 Hz,1H), 6.75 (d, J=9.6 Hz, 1H), 6.65 (d, J=9.1 Hz, 1H), 3.80 (quin, J=8.8Hz, 1H), 3.69 (s, 3H), 3.24-3.28 (m, 1H), 2.54-2.62 (m, 4H). m/z (ESI,positive ion) 531.0 (M+H)⁺.

Example 39:Trans-(P)-1-(5-Fluoro-2-Methoxy-4-((1R,3R)-3-(Trifluoromethyl)Cyclobutyl)Phenyl)-2-Oxo-N-(Pyridazin-3-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

The title compound was prepared according to the method of Example 35,by using(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide(382 mg, 0.756 mmol) in place of(P)-1-(4-Bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.The sample was purified using two sequential Chiralcel, 3×15 cm columns.The mobile phase was run under isocratic conditions; supercritical CO₂with 20% methanol; flow rate: 80 mL/min. The sample was further purifiedvia silica gel column chromatography (gradient elution 0-100%EtOAc:heptane with 10% dichloromethane co-eluent) to affordtrans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide(59.5 mg, 0.108 mmol, 14% yield over 2 steps) as a white solid. ¹H NMR(500 MHz, DMSO-d₆) δ ppm 14.23-14.74 (m, 1H), 8.24-8.37 (m, 2H), 8.18(d, J=9.6 Hz, 1H), 7.88-7.98 (m, 1H), 7.80-7.86 (m, 1H), 7.68 (br dd,J=9.5, 3.8 Hz, 1H), 7.32 (d, J=7.0 Hz, 1H), 7.29 (d, J=9.9 Hz, 1H), 6.75(d, J=9.6 Hz, 1H), 6.70 (d, J=9.1 Hz, 1H), 3.95 (quin, J=9.0 Hz, 1H),3.71 (s, 3H), 3.24-3.28 (m, 1H), 2.56-2.70 (m, 4H). m/z (ESI, positiveion) 549.0 (M+H)⁺.

Example 40:(P)-1-(5-Fluoro-2-Methoxy-4-((1R,3R)-3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

Step 1:(P)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-N-(2,4-Dimethoxybenzyl)-7-Fluoro-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A 250 mL round-bottom flask was charged with (P)-perfluorophenyl1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate(5.0 g, 8.17 mmol) and N-(2,4-dimethoxybenzyl)isoxazol-3-amine (2.37 g,10.1 mmol). The flask was purged with nitrogen for 5 minutes beforetetrahydrofuran (20 mL) was introduced. The resultant mixture was cooledto −78° C. in dry ice-acetone bath and sodium tert-pentoxide (30%solution in THF, 5.0 mL, 12.5 mmol) was added dropwise. The reactionmixture then stirred for 15 min. An aqueous solution of ammoniumchloride (5 M) was introduced, the resultant mixture was allowed to warmto ambient temperature, and was then extracted with EtOAc. The organiclayer was dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography (BIOTAGE®, 100 g Silica Cartridge, eluent: 0-80%ethyl acetate in heptane with 10% dichloromethane additive) to afford(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-7-fluoro-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(1.92 g, 2.90 mmol, 35.5% yield) as a white solid. m/z (ESI) 662.0 and664.0 (M+H)⁺.

Step 2:(P)—N-(2,4-Dimethoxybenzyl)-7-Fluoro-1-(5-Fluoro-2-Methoxy-4-((1R,3R)-3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A 100 mL round-bottom flask equipped with a reflux condenser was chargedwith magnesium turnings (796 mg, 32.8 mmol) and purged with nitrogen for15 minutes. Iodine (151 mg, 0.596 mmol) was introduced and the flask waswarmed with a heat gun until the iodine visibly sublimated. Aftercooling to ambient temperature, a slight vacuum was applied to removeexcess of iodine. Tetrahydrofuran (12.5 mL) was introduced.Trans-1-bromo-3-(trifluoromethyl)cyclobutane (5.00 g, 24.6 mmol,Enamine, LLC) was then slowly added to the stirred reaction mixture viasyringe, resulting in a slight exotherm and loss of iodine color. Thereaction vessel was submerged in an ice/water bath as needed to preventexcessive exotherm. After stirring for 1 h, tetrahydrofuran (12.5 mL)was added. After an additional 1 h, zinc chloride solution (1.9 M in2-methyltetrahydrofuran, 14.0 mL, 26.6 mmol, Sigma-Aldrich Corporation)was added, resulting in the formation of a white precipitate. Theresulting mixture was stirred at ambient temperature overnight and usedwithout further manipulation. The organozinc solution was titration withiodine to provide an estimated concentration of 0.33 M. A separate 100mL round-bottom flask was charged with2-dicyclohexylphosphino-2′,6′-dimethylamino-1,1′-biphenyl (0.501 g, 1.15mmol),(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(2,4-dimethoxybenzyl)-7-fluoro-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(1.90 g, 2.87 mmol), palladium(II) acetate (129 mg, 0.57 mmol), andtetrahydrofuran (14.0 mL). The reaction mixture was sparged withnitrogen for 10 minutes. A portion of the(3-(trifluoromethyl)cyclobutyl)zinc(II) bromide solution prepared above(10 mL, 3.30 mmol) was added dropwise via syringe to the reactionmixture. Following addition, the resultant mixture was warmed to 50° C.After 1.5 h, water was introduced and the mixture was extracted withethyl acetate. The organic layer was dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by flash column chromatography (BIOTAGE®, 100 g SilicaCartridge, eluent: 0-50% ethyl acetate in heptane with 10% DCM additive)to afford(P)—N-(2,4-dimethoxybenzyl)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(2.0 g, 2.83 mmol, 99% yield). m/z (ESI) 705.8 (M+H)⁺.

Step 3:(P)-7-Fluoro-1-(5-Fluoro-2-Methoxy-4-((1R,3R)-3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A 50 mL round-bottomed flask was charged with(P)—N-(2,4-dimethoxybenzyl)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(2.0 g, 2.83 mmol), dichloromethane (12 mL), and trifluoroacetic acid(2.8 mL). The reaction mixture stirred at room temperature for 2 hoursbefore the solvent was removed under a stream of nitrogen. The residuewas purified by flash column chromatography (BIOTAGE®, 25 g SilicaCartridge, eluent: 0-70% ethyl acetate in heptane with 10% DCMadditive). Fractions containing desired product were combined, thesolvent was removed under reduced pressure, and the residue (1.5 g) wasfurther purified by SFC using a Chiralpak AD-H column (3×25 cm, 5micron), with a mobile phase of 20% ethanol using a flowrate of 160mL/min to afford(P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(844 mg, 1.52 mmol, 54% yield), ¹H NMR (500 MHz, DMSO-d₆,) δ: 11.97 (brs, 1H), 8.72 (d, J=1.8 Hz, 1H), 8.46 (d, J=7.8 Hz, 1H), 8.22 (d, J=9.7Hz, 1H), 7.23-7.40 (m, 2H), 6.75 (d, J=9.7 Hz, 1H), 6.53 (d, J=11.9 Hz,1H), 6.39 (d, J=1.8 Hz, 1H), 3.86-4.02 (m, 1H), 3.73 (s, 3H), 3.17-3.30(m, 1H), 2.53-2.75 (m, 4H). m/z (ESI) 556.0 (M+H)⁺.

Example 41:(P)-1-(4-(3,3-Difluorocyclobutyl)-5-Fluoro-2-Methoxyphenyl)-7-Fluoro-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

Step 1: (P)-Perfluorophenyl1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-7-Fluoro-2-Oxo-1,2-Dihydroquinoline-6-Sulfonateand (M)-Perfluorophenyl1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-7-Fluoro-2-Oxo-1,2-Dihydroquinoline-6-Sulfonate

rac-Perfluorophenyl1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate(see Intermediate AB) (257 g, 420 mmol) was purified by SFC via an RegisWhelk-O s,s, 5×15 cm, 5 μm column; a mobile phase of 40%isopropanol/dichloromethane (1:1 mix) using a flowrate of 350 mL/min; togenerate (P)-perfluorophenyl1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonateas the first eluting peak (123 g, 201 mmol) and (M)-perfluorophenyl1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonateas the second eluting peak (137 g, 224 mmol).

Step 2:(P)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-7-Fluoro-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A 3 L three-neck round-bottom flask equipped with thermocouple, overheadstirrer, addition funnel, and nitrogen inlet was charged with(P)-perfluorophenyl1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate(175 g, 286 mmol), N-(4-methoxybenzyl)isoxazol-3-amine (64.2 g, 314mmol), and 2-methyltetrahydrofuran (953 mL). The reaction vessel wasthen purged with nitrogen. The reaction mixture was cooled to 0° C. Theaddition funnel was charged with a 30% solution of sodium tert-pentoxidein THF (149 mL, 372 mmol) and added dropwise to the stirred reactionmixture over 15 mins. After 10 min, an aqueous solution of HCl (2 N, 200mL) was added to the reaction mixture at 0° C. The resultant mixture wasallowed to warm to room temperature and the layers were separated. Theaqueous layer was extracted with and EtOAc (2×100 mL). The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by SFC via a Regis Whelk-O s,s 5×15 cm, 5 μm column; amobile phase of 40% methanol/dichloromethane (1:1 mix) using a flowrateof 350 mL/min to afford(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(148 g, 234 mmol, 82% yield). m/z (ESI) 632.0/634.0 (M+H)+.

Step 3:(P)-7-Fluoro-1-(5-Fluoro-2-Methoxy-4-(5,8-Dioxaspiro[3.4]Octan-2-Yl)Phenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

An oven-dried 100 mL three-neck round-bottom flask was charged with zincdust (10.3 g, 158 mmol) and lithium chloride solution in THF (0.5 M,45.0 mL, Sigma Aldrich). The mixture was stirred at 50° C. under astream of nitrogen until the reaction volume was reduced by half1,2-Dibromoethane (0.74 g, 0.34 mL, 3.95 mmol) was introduced and thereaction mixture was warmed to 50° C. Once the internal temperaturereached 50° C., the reaction mixture was held at that temperature for 20min, then cooled to room temperature. Chlorotrimethylsilane (0.43 g,0.50 mL, 3.95 mmol) was added and the reaction mixture was warmed to 50°C. and held for 20 min, then cooled to room temperature. A solution ofiodine (0.40 g, 1.58 mmol) in THF (1.0 mL) was then added and thereaction mixture was warmed to 50° C. and held for 20 min.2-Bromo-5,8-dioxaspiro[3.4]octane (15.3 g, 15.3 mL, 79.0 mmol, Enamine,LLC) was added and the reaction mixture stirred at 50° C. for 48 hours.The reaction mixture was then cooled to room temperature and theresidual zinc dust was allowed to settle before the supernatant solutionwas removed via syringe and used without further purification. Aseparate oven-dried 100 mL round-bottom flask was charged with palladium(II) acetate (0.36 g, 1.58 mmol), CPhos (1.38 g, 3.16 mmol), and THF (10mL). A solution of(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(10.0 g, 15.8 mmol) in THF (10 mL) was then introduced and the resultantmixture was sparged with nitrogen for 10 min. The previously preparedsolution of organozinc complex was then added to the reaction mixturevia syringe and the resultant mixture stirred at 50° C. After 2 h,methanol (5 mL) and silica gel (about 25 g) were added to the reactionmixture and the volatiles were removed under reduced pressure. Thesilica-adsorbed material was purified by flash column chromatography(ISCO CombiFlash, 330 g Silica Cartridge, eluent: 0-70% ethylacetate/ethanol (3:1 mix) gradient in heptane/DCM (9:1 mix)) to afford(P)-7-fluoro-1-(5-fluoro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(9.56 g, 14.4 mmol, 91% yield). m/z (ESI) 666.2 (M+H)+.

Step 4:(P)-7-Fluoro-1-(5-Fluoro-2-Methoxy-4-(3-Oxocyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A 100 mL round-bottom flask was charged with(P)-7-fluoro-1-(5-fluoro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(9.56 g, 14.4 mmol) and THF (20 mL). An aqueous solution of HCl (6 M, 10mL) was introduced, and the resultant reaction mixture was warmed to 40°C. After 2 h, the reaction mixture was cooled to room temperature beforea saturated sodium bicarbonate solution (100 mL) and DCM (100 mL) wereintroduced. The layers were separated and the aqueous layer wasextracted with DCM (2×50 mL). The combined organic layers were driedover anhydrous magnesium sulfate, filtered, concentrated under reducedpressure, and purified by flash column chromatography (ISCO CombiFlash,330 g Silica Cartridge, eluent: 0-70% ethyl acetate/ethanol (3:1 mix)gradient in heptane/DCM (9:1 mix)) to afford(P)-7-fluoro-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(8.56 g, 13.8 mmol, 87% yield). m/z (ESI) 622.0 (M+H)+.

Step 5:(P)-1-(4-(3,3-Difluorocyclobutyl)-5-Fluoro-2-Methoxyphenyl)-7-Fluoro-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A 250 mL round-bottom flask was charged with(P)-7-fluoro-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(5.00 g, 8.04 mmol) and DCM (40.2 mL). The reaction mixture was cooledto 0° C. in an ice-water bath before DAST (25.9 g, 21.3 mL, 161 mmol)was added slowly via syringe. The ice-water bath was removed and thereaction mixture was allowed to warm to room temperature. After 2 h, thereaction mixture was carefully transferred into a mixture of a saturatedaqueous solution of sodium bicarbonate and ice (about 300 mL, 1:1). Thelayers were separated and the aqueous layer was extracted with DCM. Thecombined organic layers were washed with brine, dried over anhydrousmagnesium sulfate, filtered, concentrated under reduced pressure, andpurified by flash column chromatography (ISCO CombiFlash, 100 g SilicaCartridge, eluent: 0-70% ethyl acetate/ethanol (3:1 mix) gradient inheptane/DCM (9:1 mix) to afford(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(4.32 g, 6.71 mmol, 83% yield). m/z (ESI) 644.0 (M+H)+.

Step 6:(P)-1-(4-(3,3-Difluorocyclobutyl)-5-Fluoro-2-Methoxyphenyl)-7-Fluoro-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A 250 mL round-bottom flask was charged with(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(9.90 g, 15.4 mmol), triethylsilane (8.94 g, 8.94 mL, 77.0 mmol), and1,1,1-trifluoroacetic acid (52.3 g, 35.1 mL, 459 mmol). The reactionmixture was warmed to 40° C. After 6 hours, the reaction mixture wasconcentrated under reduced pressure and carefully poured into asaturated aqueous solution of sodium bicarbonate. The mixture wasextracted with EtOAc (3×) and the combined organic layers were washedwith brine, dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure. The product was azeotroped withheptane (3×70 mL) and purified by flash column chromatography (BIOTAGE®,100 g Silica Cartridge, eluant: 0-50% EtOAc/heptane) to afford(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(6.85 g, 13.1 mmol, 85% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ: 11.8-12.1(m, 1H), 8.70 (d, 1H, J=1.7 Hz), 8.44 (d, 1H, J=7.7 Hz), 8.22 (d, 1H,J=9.6 Hz), 7.33 (d, 1H, J=10.0 Hz), 7.24 (d, 1H, J=6.9 Hz), 6.74 (d, 1H,J=9.7 Hz), 6.51 (s, 1H), 6.54 (s, 1H), 6.37 (d, 1H, J=1.7 Hz), 3.72 (s,3H), 3.62 (br t, 1H, J=8.8 Hz), 2.9-3.1 (m, 4H). m/z (ESI) 524.0 (M+H)+.

Example 42:(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Bicyclo[1.1.1]Pentan-1-Yl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

Step 1:(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Bicyclo[1.1.1]Pentan-1-Yl)Phenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-DihydroQuinoline-6-Sulfonamide

An oven-dried 40-mL vial was charged with2′-(dicyclohexylphosphino)-N²,N²,N⁶,N⁶-tetramethyl-[1,1′-biphenyl]-2,6-diamine(32.9 mg, 0.075 mmol) and palladium(II) acetate (8.47 mg, 0.038 mmol)and1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(464 mg, 0.755 mmol). The reaction mixture was sparged with nitrogen for15 min, and then (3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)zinc(II)iodide solution (272 mg, 0.83 mmol) was added after filtering through a0.45 micron PTFE filter. The reactions were stirred at 50° C. After 2hours, the reaction mixture was quenched with saturated aqueous sodiumbicarbonate and partitioned between water and ethyl acetate; the organiclayer was dried over sodium sulfate and concentrated. The initialproduct was purified via column chromatography (elution with 0-40% ethylacetate in heptane with 10% dichloromethane) to provide(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(128 mg, 0.191 mmol, 25% yield) as a brown foam. m/z (ESI, positive ion)670.0 (M+H)⁺.

Step 2:(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Bicyclo[1.1.1]Pentan-1-Yl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(190 mg, 0.284 mmol) was dissolved in TFA (1.2 mL) and stirred at 40° C.After completion, the reaction was concentrated, and subjected toreverse phase purification, eluted with 35 to 80% acetonitrile in water(with 0.1% formic acid) to provide(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(112 mg, 0.204 mmol, 72% yield) as a white solid after lyophilization.¹H NMR (500 MHz, CHLOROFORM-d,) 6 ppm 8.28 (d, J=1.7 Hz, 1H), 8.13 (d,J=2.1 Hz, 1H), 7.80 (d, J=9.6 Hz, 1H), 7.76 (dd, J=2.2, 9.0 Hz, 1H),7.72 (s, 1H), 6.94 (d, J=9.1 Hz, 1H), 6.87 (d, J=9.7 Hz, 1H), 6.8-6.8(m, 1H), 6.77 (d, J=9.0 Hz, 1H), 6.62 (d, J=1.8 Hz, 1H), 3.73 (s, 3H),2.43 (s, 6H). m/z (ESI, positive ion) 550.0 (M+H)+.

Example 43:Trans-(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

Step 1:Trans-(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(4-Methoxybenzyl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A vial was charged with(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.494 g, 0.804 mmol), palladium(ii) acetate (0.023 g, 0.102 mmol), and2-dicyclohexylphosphino-2′,6′-dimethylamino-1,1′-biphenyl (0.076 g,0.173 mmol). The resulting mixture was sealed via septum cap and spargedwith nitrogen for 10 minutes prior to the addition of tetrahydrofuran(3.09 mL). trans-(3-(trifluoromethyl)cyclobutyl)zinc(II) bromide (9.46mL, 1.182 mmol) solution was then dropwise via syringe. After completeaddition, the reaction was warmed to 50° C. and stirred at thistemperature for 1.25 hours. After cooling to ambient temperature, thereaction was quenched with 5 M aqueous ammonium chloride solution. Themixture was extracted with ethyl acetate (2X). After removal of solvent,the residue was purified by flash column chromatography (elution 0-50%3:1 ethyl acetate:ethanol in heptane with 10% dichloromethane additive)to affordtrans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.384 g, 0.584 mmol, 73% yield). m/z (ESI, positive ion) 658.0 (M+H)+.

Step 2:Trans-(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.384 g, 0.584 mmol) was dissolved in 1,1,1-trifluoroacetic acid (1.348g, 1.348 mL, 11.82 mmol) and stirred under a nitrogen atmosphere at 40°C. for 2.5 hours. After cooling to ambient temperature, excess TFA wasremoved under vacuum and the resulting solid was triturated with diethylether and filtered. The initial product was purified by columnchromatography (gradient elution of 0-100% EtOAc in heptane with 10%dichloromethane as additive) to afford(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(70.8 mg, 0.132 mmol, 23% yield). ¹H NMR (500 MHz, DMSO-d6) δ ppm 12.13(br s, 1H), 8.31 (d, J=2.21 Hz, 1H), 8.17 (d, J=9.60 Hz, 1H), 7.84 (dd,J=8.89 Hz, 2.14 Hz, 1H), 7.59 (d, J=1.56 Hz, 1H), 7.34-7.25 (m, 3H),6.75 (d, J=9.32 Hz, 1H), 6.70 (d, J=8.76 Hz, 1H), 3.95 (quin, J=8.99 Hz,1H), 3.72 (s, 3H), 3.29-3.21 (m, 1H), 2.75-2.56 (m, 4H). m/z (ESI,positive ion) 538.0 (M+H)+.

Examples 44 & 45:1-(5-Fluoro-2-Methoxy-4-((1R,3R)-3-(Trifluoromethoxy)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamideand1-(5-Fluoro-2-Methoxy-4-((1R,3R)-3-(Trifluoromethoxy)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

Step 1:(P)-1-(5-Fluoro-2-Methoxy-4-(3-Oxocyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A vial was charged with(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.850 g, 1.383 mmol), diacetoxypalladium (0.040 g, 0.180 mmol), and2′-(dicyclohexylphosphaneyl)-N2,N2,N6,N6-tetramethyl-[1,1′-biphenyl]-2,6-diamine(0.133 g, 0.304 mmol). The resulting mixture was sealed via septum capand sparged with nitrogen for 10 minutes prior to the addition oftetrahydrofuran (6.92 mL). (5,8-dioxaspiro[3.4]octan-2-yl)zinc(II)bromide solution (1.660 mmol) was then added dropwise via syringe. Aftercomplete addition, the reaction was warmed to 50° C. and stirred for1.25 hours. After cooling to ambient temperature, the reaction wasquenched with 5 M aqueous ammonium chloride solution and the productextracted with ethyl acetate (2×). The combined organic phases weredried over MgSO₄, filtered and concentrated. The residue was purified byflash column chromatography (elution 0-50% 3:1 ethyl acetate:ethanol inheptane with 10% dichloromethane as additive) to afford(P)-1-(5-fluoro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.896 g, 1.383 mmol, 100% yield). m/z (ESI, positive ion) 648.0 (M+H)+.

(P)-1-(5-fluoro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.896 g, 1.383 mmol) was dissolved in THF (13.8 ml). Hydrogen chloride(1 N in water) (6.92 mL, 6.92 mmol) was added and the reaction wasstirred at 50° C. overnight. The reaction was diluted with ethyl acetateand washed with water. The aqueous layer was extracted with ethylacetate, and the combined organic layers were washed with brine, driedwith MgSO₄, filtered, and concentrated. The(P)-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.835 g, 1.383 mmol, 100% yield) thus obtained was used as such in thenext step. m/z (ESI, positive ion) 604.0 (M+H)+.

Step 2:(P)-1-(5-Fluoro-4-(3-Hydroxycyclobutyl)-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A vial was charged with(P)-1-(5-fluoro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.835 g, 1.383 mmol) in methanol (6.92 mL) and THF (6.92 mL) at 0° C.was added portionwise sodium tetra hydroborate (0.052 g, 1.383 mmol).The reaction mixture was stirred 15 minutes a 0° C. and then 30 minutesat RT. The reaction mixture was quenched with water and extracted withDCM (3×). The combined organic phases were concentrated in vacuo. Theinitial product was purified by column chromatography (gradient elution0-40% EtOAc/EtOH (3/1) in heptanes with 10% dichloromethane as additive)to afford(P)-1-(5-fluoro-4-(3-hydroxycyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.454 g, 0.749 mmol, 54% yield). m/z (ESI, positive ion) 606.0 (M+H)+.

Step 3:Cis-(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethoxy)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-SulfonamideandTrans-(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethoxy)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A vial was charged with silver trifluoromethanesulfonate (0.513 g, 1.996mmol), selectfluor (0.354 g, 0.998 mmol), potassium fluoride (0.155 g,2.66 mmol) and(P)-1-(5-fluoro-4-(3-hydroxycyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.4029 g, 0.665 mmol) in a nitrogen-filled glovebox. Then anhydrousethyl acetate (3.33 mL), 2-fluoropyridine (0.194 g, 0.172 mL, 1.996mmol) and trimethyl(trifluoromethyl)silane (0.284 g, 0.295 mL, 1.996mmol) were added successively under nitrogen atmosphere. The reactionmixture was stirred at room temperature for 18 hours. The reactionmixture was filtered through a plug of silica (eluted with ethylacetate). The filtrate was concentrated, and the product was purified bycolumn chromatography (gradient elution 0-40% EtOAc-EtOH (3/1) inheptanes with 10% dichloromethane as additive) to give(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(358 mg, 0.531 mmol, 80% yield). m/z (ESI, positive ion) 674.0 (M+H)+.

The two isomers were separated by SFC via two Chiralpak AD-H, 5 μmcolumns (3×25 cm+3×15 cm) with a mobile phase of 25% ethanol using aflowrate of 80 mL/min. Peak 1 was assigned ascis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(28.8 mg) and peak 2 was assigned astrans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(228.4 mg).

Step 4:1-(5-Fluoro-2-Methoxy-4-((1R,3R)-3-(Trifluoromethoxy)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamideand1-(5-Fluoro-2-Methoxy-4-((1R,3R)-3-(Trifluoromethoxy)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.0288 g, 0.043 mmol), triethylsilane (0.044 g, 0.061 mL, 0.375 mmol),and trifluoracetic acid (0.370 g, 0.242 mL, 3.25 mmol) were combinedunder nitrogen. The reaction mixture was stirred at 50° C. for 5 hours.The mixture was cooled, diluted with heptane and evaporated to drynessunder reduced pressure. The product was then purified by flashchromatography (gradient elution 0-40% ethyl acetate/EtOH (3:1) inheptane with 10% dichloromethane as additive) to affordcis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(13.3 mg, 0.024 mmol, 56% yield). ¹H NMR (500 MHz, DMSO-d6) δ ppm 11.62(s, 1H), 8.71 (s, 1H), 8.34 (d, J=2.08 Hz, 1H), 8.20 (d, J=9.60 Hz, 1H),7.83 (dd, J=8.95, 2.21 Hz, 1H), 7.32-7.27 (m, 2H), 6.78 (d, J=9.38 Hz,2H), 6.43 (d, J=1.43 Hz, 1H), 5.11 (t, J=5.77 Hz, 1H), 4.00-3.92 (m,1H), 3.71 (s, 3H), 2.83-2.71 (m, 4H), 2.55-2.52 (m, 1H). m/z (ESI,positive ion) 554.0 (M+H)+.

trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.2284 g, 0.339 mmol), triethylsilane (0.346 g, 0.481 mL, 2.98 mmol),and trifluoracetic acid (2.94 g, 1.920 mL, 25.8 mmol) were combinedunder nitrogen. The reaction mixture was stirred at 50° C. for 5 hours.The mixture was cooled, diluted with heptane and evaporated to drynessunder reduced pressure. The product was then purified by flashchromatography (gradient elution 0-40% ethyl acetate/EtOH (3:1) inheptane with 10% dichloromethane as additive) to affordtrans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.1623 g, 0.293 mmol, 86% yield). ¹H NMR (500 MHz, DMSO-d6) δ ppm 11.62(s, 1H), 8.72 (d, J=1.82 Hz, 1H), 8.35 (d, J=2.21 Hz, 1H), 8.20 (d,J=9.60 Hz, 1H), 7.83 (dd, J=9.02, 2.27 Hz, 1H), 7.30 (d, J=9.99 Hz, 1H),7.23 (d, J=6.62 Hz, 1H), 6.78 (d, J=9.47 Hz, 2H), 6.44 (d, J=1.82 Hz,1H), 4.92 (quin, J=7.40 Hz, 1H), 3.38 (tt, J=10.46, 7.51 Hz, 1H),3.32-3.25 (m, 3H), 2.84 (dquin, J=12.05, 6.07, 6.07, 6.07, 6.07 Hz, 2H),2.55-2.52 (m, 1H), 2.47-2.41 (m, 1H). m/z (ESI, positive ion) 554.0(M+H)+.

Example 46:Trans-(P)-5-Fluoro-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

Step 1: 4-Bromo-3-Fluoro-2-Iodoaniline

To a solution of 2-iodo-3-fluoroaniline hydrogen chloride (6.45 g, 23.59mmol) and N,N′-diisopropylethylamine (3.05 g, 4.11 mL, 23.59 mmol) in N,N-dimethylformamide (59.0 mL) was added N-bromosuccinimide (4.20 g,23.59 mmol). After 20 minutes, the reaction was quenched with water. Themixture was extracted with ethyl acetate. The organic layer wasseparated, dried over magnesium sulfate, filtered and concentrated underreduced pressure to obtain the initial product which was purified bycolumn chromatography (BIOTAGE® ISOLERA ONE, BIOTAGE SFÄR SILICA 50 g,0-30% ethyl acetate in heptane) to afford 4-bromo-3-fluoro-2-iodoaniline(6.8 g, 21.52 mmol, 91% yield) as a tan, almost copper-colored solid.m/z (ESI, positive ion) 315.8 (M+H)+.

Step 2: Ethyl (E)-3-(6-Amino-3-Bromo-2-Fluorophenyl)Acrylate

A 100 mL flask was charged with sodium hydrogen carbonate (4.19 g, 49.9mmol), ethyl acrylate (2.096 g, 2.355 mL, 20.94 mmol), and palladium(ii) acetate (0.090 g, 0.399 mmol). A solution of4-bromo-3-fluoro-2-iodoaniline (6.3 g, 19.94 mmol) in N,N-dimethylformamide (13.29 mL) was added to the reaction mixture. Thereaction was stirred at 100° C. under nitrogen for 3 hours. The reactionwas diluted with ethyl acetate and filtered through CELITE. The filtratewas concentrated under reduced pressure to obtain the initial productwhich was purified by column chromatography to give ethyl(E)-3-(6-amino-3-bromo-2-fluorophenyl)acrylate (5.92 g, 20.55 mmol, 103%yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 7.50-7.68 (m, 1H), 7.29 (t,J=8.3 Hz, 1H), 6.34-6.60 (m, 2H), 6.07 (s, 1H), 3.98-4.24 (m, 2H), 3.35(br s, 1H), 1.08-1.36 (m, 3H).

Step 3: Ethyl (E)-3-(6-Amino-3-(Benzylthio)-2-Fluorophenyl)Acrylate

A 250 mL round-bottom flask was charged with ethyl(E)-3-(6-amino-3-bromo-2-fluorophenyl)acrylate (4.0 g, 13.88 mmol),1,4-dioxane (34.7 mL) and 1,1′-dimethyltriethylamine (3.59 g, 4.85 mL,27.8 mmol). The flask was sealed and sparged with nitrogen for 20minutes. In a separate 20 mL vial,bis[tris(dibenzylideneacetone)palladium(0)](0.890 g, 0.972 mmol) and(5-diphenylphosphanyl-9,9-dimethylxanthen-4-yl)-diphenylphosphane (1.125g, 1.944 mmol) were added. The vial was sparged with nitrogen for 5minutes prior to the addition of 1,4-dioxane (5 mL). This catalystsolution was transferred via syringe to the acrylate-containing flask.Then 1-toluenethiol (1.379 g, 1.379 mL, 11.11 mmol) was added in oneportion. The mixture was stirred at 80° C. for 16 hours. The reactionwas cooled and filtered over CELITE. The CELITE was washed with ethylacetate. The solvent was removed under reduced pressure. The residue waspurified by column chromatography (BIOTAGE® Isolera One, BIOTAGE® SNAPUltra 100 g, 0-30% ethyl acetate in heptane) to afforded ethyl(E)-3-(6-amino-3-(benzylthio)-2-fluorophenyl)acrylate (2.78 g, 8.39mmol, 60% yield) as a yellow orange solid. m/z (ESI, positive ion) 332.2(M+H)+.

Step 4: Ethyl(E)-3-(3-(Benzylthio)-6-((4-Bromo-5-Fluoro-2-Methoxyphenyl)Amino)-2-Fluorophenyl)Acrylate

A 40 mL vial was charged with ethyl(E)-3-(6-amino-3-(benzylthio)-2-fluorophenyl)acrylate (0.876 g, 2.64mmol), 1-bromo-2-fluoro-4-iodo-5-methoxybenzene (1.07 g, 3.23 mmol), andcesium carbonate (2.58 g, 7.93 mmol). Toluene (8.81 mL) was added to thevial. The mixture was sparged with nitrogen for 20 minutes before tris(dibenzylideneacetone)-dipalladium(0) (0.194 g, 0.194 mL, 0.211 mmol)and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.245 g, 0.423mmol) were quickly added. After sparging with nitrogen for an additional5 minutes, the reaction was warmed to 110° C. After stirring for 16hours, the reaction was cooled to ambient temperature, diluted withdichloromethane, and filtered over CELITE. Solvent was removed underreduced pressure. The residue was purified by column chromatography(BIOTAGE® ISOLERA ONE, BIOTAGE SFÄR SILICAHC D 25 g, 0-40% ethyl acetatein heptane) to afforded ethyl(E)-3-(3-(benzylthio)-6-((4-bromo-5-fluoro-2-methoxyphenyl)amino)-2-fluorophenyl)acrylate(0.600 g, 1.123 mmol, 43% yield) as a yellow solid. m/z (ESI, positiveion) 535.8 (M+H)+.

Step 5:6-(Benzylthio)-1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-5-Fluoroquinolin-2(1H)-One

Ethyl(E)-3-(3-(benzylthio)-6-((4-bromo-5-fluoro-2-methoxyphenyl)amino)-2-fluorophenyl)acrylate(1.44 g, 2.69 mmol) was dissolved in methanol (33 mL). Sodium methoxide,25 wt % solution in methanol (0.582 g, 0.616 mL, 2.69 mmol) was added atambient temperature. The reaction was warmed to 60° C. and stirred atthis temperature for 2 hours. The reaction was cooled to ambienttemperature and quenched by the addition of water. The product wasextracted with ethyl acetate (2×). The organic layer was separated andsolvent was removed in vacuo. The residue was purified by columnchromatography (BIOTAGE® Isolera One, BIOTAGE® Sfar Silica HC D 50 g,0-40% Ethyl acetate in heptane with 10% dichloromethane as additive) toprovided6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoroquinolin-2(1H)-one(0.717 g, 1.468 mmol, 55% yield) as an off white solid. m/z (ESI,positive ion) 490.0 (M+H)+.

Step 6 & 7: Perfluorophenyl1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-5-Fluoro-2-Oxo-1,2-Dihydroquinoline-6-Sulfonate

A 40 mL vial was charged with6-(benzylthio)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoroquinolin-2(1H)-one(0.710 g, 1.454 mmol), acetonitrile (7.04 mL), acetic acid (0.134 mL),and water (0.095 mL). The reaction was cooled to 0° C. by means of anice bath before 1,3-dichloro-5,5-dimethyl-2,4-imidazolidinedione (0.430g, 2.181 mmol) was added in one portion. After 10 minutes,pentafluorophenol (0.321 g, 1.745 mmol) and then triethylamine,anhydrous (0.588 g, 0.817 mL, 5.82 mmol) were added. After 1 hour thereaction was quenched with 2 M aqueous HCl and was extracted with ethylacetate. The organic layer was separated and solvent was removed invacuo. The residue was purified by column chromatography (BIOTAGE®Isolera One, BIOTAGE® Sfar 25 g silica HC D, 0-40% ethyl acetate inheptane with 10% dichloromethane as additive) to provide perfluorophenyl1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate(0.676 g, 1.104 mmol, 76% yield) as a white solid. m/z (ESI, positiveion) 614.0 (M+H)+.

Steps 8:1-(4-Bromo-5-Fluoro-2-Methoxyphenyl)-5-Fluoro-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A 40 mL vial was charged with perfluorophenyl1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoro-2-oxo-1,2-dihydroquinoline-6-sulfonate(0.676 g, 1.104 mmol) and N-(4-methoxybenzyl)isoxazol-3-amine (0.271 g,1.325 mmol). The vial was purged with nitrogen for 5 minutes prior tothe addition of tetrahydrofuran (2.208 mL). The reaction was then cooledto −78° C. and sodium tert-pentoxide, 30% solution in thf (0.574 mL,1.435 mmol) was slowly added. After 10 minutes the reaction was warmedto 0° C. prior to quenching the reaction with 5 M aqueous ammoniumchloride solution. The mixture was extracted with ethyl acetate. Theorganic layer was separated and solvent was removed under reducepressure. The residue was purified by column chromatography (BIOTAGE®ISOLERA ONE, BIOTAGE SFÄR SILICA 25 g, 0-50% ethyl acetate in heptanewith 10% dichloromethane as additive) to provides1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoro-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.302 g, 0.478 mmol, 43% yield) as a white solid. m/z (ESI, positiveion) 634.0 (M+H)+.

Step 9:5-Fluoro-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A 40 mL vial was charged with1-(4-bromo-5-fluoro-2-methoxyphenyl)-5-fluoro-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.320 g, 0.506 mmol), palladium(ii) acetate (0.011 g, 0.051 mmol), and2′-(dicyclohexylphosphino)-N²,N²,N⁶,N⁶-tetramethyl-[1,1′-biphenyl]-2,6-diamine(0.044 g, 0.101 mmol). The vial was sealed and sparged with nitrogen for5 minutes. Tetrahydrofuran (2.53 mL) was then added, followed by theaddition of (3-(trifluoromethyl)cyclobutyl)zinc(II) bromide (1.381mmol). The reaction was then stirred at 50° C. for 1.5 hours. Thereaction was cooled to ambient temperature, quenched with 5M aqueousammonium chloride solution, and extracted with ethyl acetate. Theorganic layer was separated and solvent was removed under reducedpressure. The residue was purified by column chromatography (BIOTAGE®ISOLERA ONE, BIOTAGE SFÄR SILICAHC D 10 g, 0-40% ethyl acetate inheptane with 10% dichloromethane as additive) to affords5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.208 g, 0.308 mmol, 61% yield) as a light pink solid. m/z (ESI,positive ion) 676.2 (M+H)+.

Step 10:5-Fluoro-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A 40 mL vial was charged with5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.208 g, 0.308 mmol), triethylsilane (0.179 g, 0.249 mL, 1.539 mmol)and 1,1,1-trifluoroacetic acid (2.282 g, 2.282 mL, 20.01 mmol). Themixture was stirred at 40° C. for 2 hours. Solvent was removed in vacuo.The mixture was purified by column chromatography (BIOTAGE® ISOLERA ONE,BIOTAGE SFÄR SILICA HC D 10 g, 0-100% ethyl acetate in heptane with 10%dichloromethane as additive) to afforded5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.153 g, 0.275 mmol, 89% yield) as an off white solid. m/z (ESI,positive ion) 556.2 (M+H)+.

Step 11:Trans-(P)-5-Fluoro-1-(5-Fluoro-2-Methoxy-4-(3-(TRIFLUOROMETHYL)CYCLOBUTYL)PHENYL)-N-(ISOXAZOL-3-YL)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.153 g, 0.275 mmol) was purified by SFC via 2 steps. Step 1: a RegisWhelk-O s,s 2×15 cm, 5 μm column; a mobile phase of 35% methanol using aflowrate of 60 mL/min; Step 2: (separation of Peak1 & Peak2): twoChiralpak AD-H, 5 μm columns(3×15 cm+3×25 cm); a mobile phase of 30%ethanol using a flowrate of 80 mL/min. Peak 1 was lyophilized to yieldtrans-(P)-5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.0305 g, 0.055 mmol, 18% yield) as a white solid. ¹H NMR (500 MHz,DMSO-d6) δ ppm 12.01 (br s, 1H), 8.72 (d, J=1.8 Hz, 1H), 8.18 (d, J=9.9Hz, 1H), 7.87 (t, J=8.1 Hz, 1H), 7.34 (s, 1H), 7.33 (d, J=3.4 Hz, 1H),6.83 (d, J=9.9 Hz, 1H), 6.59 (d, J=9.2 Hz, 1H), 6.37 (d, J=1.8 Hz, 1H),3.95 (t, J=9.0 Hz, 1H), 3.73 (s, 3H), 3.22-3.28 (m, 1H), 2.55-2.72 (m,4H). m/z (ESI, positive ion) 556.2 (M+H)+.

Example 47:(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Bicyclo[1.1.1]Pentan-1-Yl)Phenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

Step 1:(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Bicyclo[1.1.1]Pentan-1-Yl)Phenyl)-N-(4-Methoxybenzyl)-2-Oxo-N-(Pyrimidin-2-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

An oven-dried 40 mL vial was charged with2′-(dicyclohexylphosphaneyl)-N²,N²,N⁶,N⁶-tetramethyl-[1,1′-biphenyl]-2,6-diamine(0.046 g, 0.106 mmol), palladium(II) acetate (0.012 g, 0.053 mmol) and(P)-1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(0.663 g, 1.060 mmol). The reaction mixture was sparged with nitrogenfor 15 minutes, and then(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)zinc(II) iodide solution(1.59 mmol) was added after filtering through a 0.45 micron PTFE filter.The reactions were stirred at 50° C. for 3 hours. The reaction mixturewas quenched with saturated aqueous sodium bicarbonate and partitionedbetween water and ethyl acetate. The organic layer was dried over sodiumsulfate and concentrated. The initial product was purified by columnchromatography (gradient elution 0-60% ethyl acetate in heptane with 10%dichloromethane as additive) to afford(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(0.241 g, 0.354 mmol, 33% yield) as a light grey foam. m/z (ESI,positive ion) 681.1 (M+H)⁺.

STEP 2:(P)-1-(5-Fluoro-2-Methoxy-4-(3-(Trifluoromethyl)Bicyclo[1.1.1]Pentan-1-Yl)Phenyl)-2-Oxo-N-(Pyrimidin-2-Yl)-1,2-Dihydroquinoline-6-Sulfonamide

(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(4-methoxybenzyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(241 mg, 0.354 mmol) was dissolved in trifluoroacetic acid (3.63 g, 2.44mL, 31.9 mmol) in a 20 mL vial and the reaction was heated to 40° C. andstirred for 2 hours. The reaction was cooled to RT. The reaction wasmade basic using saturated NaHCO₃ solution, extracted withdichloromethane. The combined organic layer was dried over sodiumsulfate and concentrated. The initial product was subjected to reversephase purification (gradient elution 25 to 70% acetonitrile in waterwith 0.1% formic acid to afford(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide(103 mg, 0.184 mmol, 52% yield) as a white solid after lyophilization.¹H NMR (CHLOROFORM-d, 500 MHz) δ ppm 10.27 (br s, 1H), 8.60 (d, J=4.9Hz, 2H), 8.43 (d, J=2.1 Hz, 1H), 8.07 (dd, J=2.1, 9.0 Hz, 1H), 7.85 (d,J=9.6 Hz, 1H), 7.00 (t, J=4.9 Hz, 1H), 6.93 (d, J=9.2 Hz, 1H), 6.85 (d,J=9.6 Hz, 1H), 6.83 (d, J=6.4 Hz, 1H), 6.77 (d, J=9.0 Hz, 1H), 3.72 (s,3H), 2.42 (s, 6H). m/z (ESI, positive ion) 561.0 (M+H)+.

Example 48:(P)-1-(5-Chloro-4-(3,3-Difluorocyclobutyl)-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

Step 1:(P)-1-(5-Chloro-2-Methoxy-4-(5,8-Dioxaspiro[3.4]Octan-2-Yl)Phenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A vial was charged with(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.500 g, 0.793 mmol), tetrahydrofuran (1.585 mL), palladium(II) acetate(0.018 g, 0.079 mmol), and2-dicyclohexylphosphino-2′,6′-dimethylamino-1,1′-biphenyl (0.069 g,0.159 mmol). 5,8-The vial was purged with nitrogen beforedioxaspiro[3.4]octan-2-ylzinc(II) bromide (0.1 M in THF, 1.110 mmol) wasadded and the reaction was stirred at 50° C. for 1 hour. The reactionwas then diluted with ethyl acetate and acidified with 1 N hydrochloricacid. The organic layer was separated and the aqueous layer wasextracted with ethyl acetate. The combined organic layers were washedwith brine, dried with sodium sulfate, filtered, and concentrated. Thematerial was purified via column chromatography (gradient elution 0-100%EtOAc:heptane) to afford(P)-1-(5-chloro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.420 g, 0.632 mmol, 80% yield). m/z (ESI, positive ion) 664.0 (M+H)⁺.

Step 2:(P)-1-(5-Chloro-2-Methoxy-4-(3-Oxocyclobutyl)Phenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

(P)-1-(5-chloro-2-methoxy-4-(5,8-dioxaspiro[3.4]octan-2-yl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.420 g, 0.632 mmol) was dissolved in dichloromethane (2 mL).Hydrochloric acid (2 N in water, 2.0 mL, 4.0 mmol) was added and thereaction was stirred at 50° C. for three days. The reaction was thendiluted with dichloromethane and washed with water. The aqueous layerwas extracted with dichloromethane. The combined organic layers werewashed with brine, dried with sodium sulfate, filtered, andconcentrated. The resulting(P)-1-(5-chloro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.330 g, 0.532 mmol, 67% yield) was used in the next step withoutfurther purification. m/z (ESI, positive ion) 620.0 (M+H)⁺.

Step 3:(P)-1-(5-Chloro-4-(3,3-Difluorocyclobutyl)-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-N-(4-Methoxybenzyl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A vial was charged with(P)-1-(5-chloro-2-methoxy-4-(3-oxocyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.330 g, 0.532 mmol), dichloromethane (1.064 mL), anddiethylaminosulfur trifluoride (2.145 g, 1.758 mL, 13.30 mmol). Thereaction was stirred for 3 hours at room temperature. The reaction wasthen poured into a round-bottom flask, diluted with dichloromethane, andsaturated aqueous sodium bicarbonate solution was carefully added untilbubbling ceased. The layers were separated, and the aqueous layer wasextracted with dichloromethane. The combined organic layers were washedwith brine, dried with sodium sulfate, filtered, and concentrated. Thematerial was purified via column chromatography (gradient elution 0-50%EtOAc:heptane) to afford(P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.350 g, 0.545 mmol, 102% yield).

Step 4:(P)-1-(5-Chloro-4-(3,3-Difluorocyclobutyl)-2-Methoxyphenyl)-N-(Isoxazol-3-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

(P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.350 g, 0.545 mmol) was dissolved in TFA (1 mL) and dichloromethane (1mL). The solution was heated to 40° C. and stirred overnight. Solventswere removed in vacuo and the residue was washed with aqueous solutionof NaHCO₃. The mixture was extracted with dichloromethane, dried overMgSO₄ and filtered. The initial product was purified via flash columnchromatography (gradient elution 0-50% EtOAc in heptane). The sample wasre-purified by SFC via a Regis Whelk-O s,s 2×15 cm, 5 μm column with amobile phase of 40% methanol using a flowrate of 70 mL/min to afford(P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.173 g, 0.331 mmol, 62% yield). ¹H NMR (600 MHz, DMSO-d6) δ ppm 11.63(br s, 1H), 8.71 (d, J=1.63 Hz, 1H), 8.35 (d, J=2.18 Hz, 1H), 8.20 (d,J=9.63 Hz, 1H), 7.83 (dd, J=8.99, 2.27 Hz, 1H), 7.54 (s, 1H), 7.30 (s,1H), 6.78 (dd, J=9.35, 5.36 Hz, 2H), 6.44 (d, J=1.82 Hz, 1H), 3.74 (s,3H), 3.67 (quin, J=8.67 Hz, 1H), 3.09 (dtt, J=18.20, 9.04, 9.04, 4.38,4.38 Hz, 2H), 3.02-2.89 (m, 2H). m/z (ESI, positive ion) 521.8 (M+H)⁺.

Example 49:Trans-(P)-1-(5-Chloro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

Step 1:Trans-(P)-1-(5-Chloro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(4-Methoxybenzyl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

A vial was charged with(P)-1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.508 g, 0.804 mmol), palladium(ii) acetate (0.023 g, 0.102 mmol), and2-dicyclohexylphosphino-2′,6′-dimethylamino-1,1′-biphenyl (0.076 g,0.173 mmol). The resulting mixture was sealed via septum cap and spargedwith nitrogen for 10 minutes prior to the addition of tetrahydrofuran(3.09 mL). (3-(trifluoromethyl)cyclobutyl)zinc(II) bromide (1.182 mmol)solution. After complete addition, the reaction was warmed to 50° C. andstirred at this temperature for 1.25 hours. After cooling to ambienttemperature, the reaction was quenched with 5 M aqueous ammoniumchloride solution. The mixture was extracted with ethyl acetate (2×).The organic layer was separated. After removal of solvent, the residuewas purified by flash column chromatography (gradient elution 0-50% 3:1ethyl acetate:ethanol in heptane with 10% dichloromethane as additive)to affordtrans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.368 g, 0.546 mmol, 68% yield). m/z (ESI, positive ion) 673.6 (M+H)+.

Step 2:Trans-(P)-1-(5-Chloro-2-Methoxy-4-(3-(Trifluoromethyl)Cyclobutyl)Phenyl)-N-(Oxazol-2-Yl)-2-Oxo-1,2-Dihydroquinoline-6-Sulfonamide

(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(4-methoxybenzyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(0.368 g, 0.546 mmol) was dissolved in 1,1,1-trifluoroacetic acid (1.348g, 1.348 mL, 11.82 mmol). The reaction was stirred under a nitrogenatmosphere at 40° C. for 2.5 hours. After cooling to ambienttemperature, excess TFA was removed in vacuo and the resulting solid wastriturated with diethyl ether and filtered. The initial product waspurified by column chromatography (gradient elution 0-100% in heptaneswith 10% dichloromethane as additive to afford trans(P)-1-(5-chloro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide(49.6 mg, 0.092 mmol, 17% yield). ¹H NMR (500 MHz, DMSO-d6) δ ppm 12.13(br s, 1H), 8.31 (d, J=2.08 Hz, 1H), 8.17 (d, J=9.60 Hz, 1H), 7.84 (dd,J=8.95, 2.21 Hz, 1H), 7.59 (d, J=1.56 Hz, 1H), 7.49 (s, 1H), 7.38 (s,1H), 7.25 (d, J=1.43 Hz, 1H), 6.75 (d, J=9.60 Hz, 1H), 6.69 (d, J=8.95Hz, 1H), 4.00 (quin, J=8.99 Hz, 1H), 3.77 (s, 3H), 3.27-3.20 (m, 1H),2.75-2.60 (m, 4H). m/z (ESI, positive ion) 554.0 (M+H)+.

BIOLOGICAL EXAMPLES

The following assays were used in testing the exemplary compounds of theinvention. Data for those examples tested in accordance with theprocedures described below are presented in Table 1 below.

Ionaworks Barracuda (DNB) Automated Patch Clamp Assay (Same Protocol forBoth Human and Mouse)

Human Nav1.7 currents were recorded in population patch-clamp mode withthe IWB automated electrophysiology system (Molecular Devices, LLC,Sunnyvale, Calif.). Spiking HEK cells (without Kir2.1 transfection) werecultured and prepared for recordings as previously described forIonWorks Quattro testing¹. The external solution consisted of thefollowing (in mM): NaCl 140, KCl 5, CaCl₂ 2, MgCl₂ 1, HEPES 10, andglucose 11, pH 7.4, with N-methyl-D-glucamine at 320 mOsmol. Theinternal solution consisted of the following (in mM): KCl 70, KF 70,MgCl₂ 0.25, HEDTA 5, and HEPES 10, pH 7.25, with Nmethyl-D-glucamine,300 mOsmol. From a holding potential of −110 mV, currents were elicitedby a train of 26 depolarizations of 150 ms duration to −20 mV at afrequency of 5 Hz. Cells were then clamped to −20 mV for a period of 4minutes in the presence of a single concentration of test compound.Following this compound incubation period, cells were clamped to −110 mVfor three seconds to recover unbound channels and put through the same26 pulse voltage protocol as above. Peak inward current during the 26thpulse to −20 mV in the presence of compound was divided by the peakinward current evoked by the 26th pulse to −20 mV in the absence ofcompound to determine percent inhibition. Concentration-response curvesof percent inhibition as a function of concentration were generated tocalculate IC₅₀ values as described in Kornecook, T. J.; Yin, R.;Altmann, S.; et al. Pharmacologic Characterization of AMG8379, a Potentand Selective Small Molecule Sulfonamide Antagonist of the Voltage-GatedSodium Channel NaV1. 7. J. Pharmacol. Exp. Ther. 2017, 362, 146-160.

Microsomal Intrinsic Clearance Assay

The purpose of this assay is to determine the intrinsic clearance oftest compound in microsomes from preclinical species and human bymonitoring the disappearance of test article over time in hepaticmicrosomes. 20 mg/mL stock, stored at −80° C. microsome was used. Listof chemical used: (1) Test article, 10 mM stock (DMSO) or powder fromsample bank; (2) Verapamil, 10 mM stock; (3) NADPH, powder (Sigma); (4)Potassium phosphate buffer, 100 mM, pH 7.4; and (5) Tolbutamide (orequivalent). Final incubation concentrations were 0.25 mg/mL microsomalprotein and 0.5 μM test article, and incubations are performed intriplicate. The typical time points for the assay were 1, 5, 10, 20, 30,and 40. The assay was carried out in 96-well format, and seriallysampled from 400 μL incubation. At the appropriate timepoints, theincubations were quenched with acetonitrile containing internal standard(tolbutamide). Tolbutamide was the default internal standard because ithas a signal by positive or negative ion mass spectrometry. The positivecontrol for microsomal intrinsic clearance assay was verapamil. Sampleswere subjected to LC-MS/MS analysis, and relative amount of compound wascalculated by peak area of compound normalized to peak area of internalstandard (A/IS). Calculations of intrinsic clearance were performed withGalileo.

Procedure:

Microsomes were removed from −80° C. freezer and thawed at roomtemperature or in 37° C. water bath. Once thawed, they were stored onice. Microsomes were added (0.53 mg/) to 0.1 M phosphate buffer and 250μL aliquot was taken per reaction. 10 mM stock of test article wasprepared in DMSO. A 1/100 portion was diluted into acetonitrile:water50:50 to make 100 μM stock. About 2.5 μL of the 100 μM test articlestock was added to each reaction to a final concentration of 1.05 μMsubstrate. (NB: At this stage, concentrations were about 2× higher thanthe final incubation conditions, to account for about 1:1 dilution withNADPH).

1.9 mM NADPH solution was prepared in 0.1 mM phosphate buffer. 4×250 μLreplicate wells of substrate and the microsomes containing 1.05 μMsubstrate and 0.53 mg/mL protein were the prepared. 3 replicate wellscontaining 210 μL 1.90 mM NADPH+1 well of buffer (−NADPH) were alsoprepared. The microsomes, 0.1 M phosphate buffer, and the test articlewere preincubated for 5 minutes at 37° C. To initiate the reaction, 190μL of the substrate was added to the wells containing NADPH, to yield afinal concentration of 0.25 mg/mL microsomes, 0.5 μM test article, and 1mM NADPH. 35 μL aliquots were removed at 1, 5, 10, 20, 30, and 40minutes. The reaction was then quenched at a 1:1 ratio with acetonitrilecontaining internal standard, placed in a Vortex mixer and centrifuged.The solution was then transferred for bioanalysis by LC-MS/MS.

Open-Field Locomotor Activity in Mice.

On the day of testing, C57B1/6 male mice were orally administered eitherNav1.7 compound or a vehicle control formulation at a dose volume of 10ml/kg. The vehicle used was 2% HPMC/1% Tween 80 pH 10 with NaOH; DIwater at pH 10 w/NaOH; or 2% HPMC/1% Tween 80 pH 2.2.

Two to three hours following test article treatment, depending on thecmax of the each Nav1.7 test compound of the invention, animals wereplaced into open-field chamber and the animal behavior was monitoredover a 30-minute period. For the Thousand Oaks Site Experiments, 16″×16″open-field chamber, KINDER SCIENTIFIC®, San Diego, Calif., was used. Forthe Cambridge Mass. Site Experiments, 16″×16″ open-field chamber, SANDIEGO INSTRUMENTS®, San Diego, Calif., was used. Locomotor activity(horizontal movement and rearing activity) parameters were measured inan automated manner via infrared photo-beam breaks.

Human CYP 3A4 Induction Assay

Cryopreserved human hepatocytes were seeded in 96-well collagen coatedplates at 70,000 cells per well in hepatocyte plating media (HPM, finalconcentrations: 1× Dulbecco's Modified Eagle's Medium, 0.1 μMdexamethasone, 10% fetal bovine serum, 1×ITS, 1×PSG) followed byincubation at 37° C. under 5% CO2 and 90% relative humidity for 2 daysto allow hepatocytes to form a confluent layer. On Day 3, hepatocyteswere treated with either test compound or rifampin (20 μM, positivecontrol for CYP3A induction) prepared in hepatocyte incubation media((HIM, final concentrations: 1× William's Medium E, 0.1 μMdexamethasone, 1×ITS, 1×PSG). Treatment was performed for 72 hours witheither 2 concentrations (2 μM or 10 μM) or a range of concentrations(0.001 μM to 100 μM) of the test compound to obtain full dose-responsecurve. Fresh media containing the relevant concentrations of the testcompound was replaced every day until the samples were processed. After72 hours of incubation, samples were processed for mRNA analysis usingbDNA technology using manufacturer's instructions (Affymetrix, Fremont,Calif.). Cell viability was tested at the end of the experiment usingMTT assay kit (Roche Diagnostics, Basel, Switzerland). Data was analyzedand presented as percent of control (POC) and E_(max) and EC₅₀ obtainedwhen appropriate according to guidance from Center for Drug Evaluationand Research (CDER), 2006, Guidance for Industry, Drug InteractionStudies Study Design, Data Analysis, and Implications for Dosing andLabeling.

Cryopreserved human hepatocytes were seeded in 96-well collagen coatedplates at 70,000 cells per well in hepatocyte plating media (HPM, finalconcentrations: lx Dulbecco's Modified Eagle's Medium, 0.1 μMdexamethasone, 10% fetal bovine serum, lx ITS, lx PSG) followed byincubation at 37° C. under 5% CO2 and 90% relative humidity for 2 daysto allow hepatocytes to form a confluent layer. On Day 3, hepatocyteswere treated with either test compound or rifampin (20 μM, positivecontrol for CYP3A induction) prepared in hepatocyte incubation media((HIM, final concentrations: 1× William's Medium E, 0.1 μMdexamethasone, 1×ITS, 1×PSG). Treatment was performed for 72 hours witheither 2 concentrations (2 μM or 10 μM) or a range of concentrations(0.001 μM to 100 μM) of the test compound to obtain full dose-responsecurve. Fresh media containing the relevant concentrations of the testcompound was replaced every day until the samples were processed. After72 hours of incubation, samples were processed for mRNA analysis usingbDNA technology using manufacturer's instructions (Affymetrix, Fremont,Calif.). Cell viability was tested at the end of the experiment usingMTT assay kit (Roche Diagnostics, Basel, Switzerland). Data was analyzedand presented as percent of control (POC) and E_(max) and EC₅₀ obtainedwhen appropriate, as described in Halladay, J. et al, 2012, An“all-inclusive” 96-well cytochrome P450 induction method: Measuringenzyme activity, mRNA levels, protein levels, and cytotoxicity from onewell using cryopreserved human hepatocytes, Pharmacological andToxicological Methods, 66:270-275.

The compounds of the present invention may also be tested in thefollowing in vivo assays.

Rat Formalin Model of Persistent Pain

On the test day, animals (Naïve, male Sprague Dawley rats) weighingbetween 260-300 g at the start of testing can be obtained from Harlan(Indianapolis, Ind.). All animals may be housed under a 12/12 hlight/dark cycle with lights on at 0600. Rodents can be housed two to acage on solid bottom cages with corn cob bedding and can have access tofood and water ad libitum. Animals should be allowed to habituate to thevivarium for at least five days before testing is begun and should bebrought into the testing room at least 30 minutes prior to dosing.Animals are pretreated with the appropriate test compound either by oralgavage or intraperitoneal injection at the desired pretreatment time(typically two hours before test onset) and then returned to their homecages. After dosing and at least 30 minutes prior to test onset, animalscan be acclimated to the individual testing chambers. At test time, eachanimal can be gently wrapped in a towel with the left hind paw exposed.A dilute solution of formalin (2.5%) in phosphate buffered saline can beinjected subcutaneously into the dorsal surface of the left hind paw ina volume to 50 μL with a 30 g needle. Immediately following injection, asmall metal band can be affixed to the plantar side of the left hind pawwith a drop of LOCTITE (adhesive). Animals may be then placed into thetesting chambers and the number of flinches can be recorded between 10to 40 minutes after formalin injection. A flinch is defined as a quickand spontaneous movement of the injected hind paw not associated withambulation. Flinches can be quantified with the aid of the AutomatedNociception Analyzer built by the University of California, San DiegoDepartment of Anesthesiology. Individual data can be expressed as a %maximal potential effect (% MPE) calculated with the following formula:(−(Individual score−Vehicle average score)/Vehicle average score))*100=%MPE

Statistical analysis can be performed by analysis of variance (ANOVA),with post-hoc analysis using Bonferroni compared to the vehicle groupfor a significant main effect. Data can be represented as mean %MPE+/−standard error for each group.

Rat Open Field Assay

On the test day, animals (Naïve, male Sprague Dawley rats) weighingbetween 260-300 g at the start of testing may be obtained from Harlan(Indianapolis, Ind.). All animals can be housed under a 12/12 hlight/dark cycle with lights on at 0600. Rodents can be housed two to acage on solid bottom cages with corn cob bedding and can have access tofood and water ad libitum. Animals should be allowed to habituate to thevivarium for at least five days before testing is begun and should bebrought into the testing room at least 30 minutes prior to dosing. In aroom separate from the testing room, animals can be pretreated with theappropriate test compound either by oral gavage or intraperitonealinjection at the desired pretreatment time (typically two hours beforetest onset) and then can be returned to their home cages until thepretreatment has elapsed. At test time, animal can be transferred to theopen field testing room in their home cages. Each animal may be placedin a separate testing chamber and the motion tracking system is started.The house lights in the testing room should be turned off and theanimals can be allowed to explore the novel open field for 30 minutes.An automated motion tracker, made by San Diego Instruments, San Diego,Calif., can be used to capture animal exploration with the aid ofinfrared photo beams to detect animal movement. These behaviors includebasic movement and vertical rearing, which can be used as the primaryendpoints for this assay. At the end of the test, house lights can beturned on and the animals should be removed from the testing apparatus.Data can be expressed as a percent change from the vehicle control usingthe following equation.

(1−(Test mean/Vehicle mean))*100=% Change.

Statistical analysis can be performed by analysis of variance (ANOVA),with post-hoc analysis using Dunnett to follow up significant maineffects.

Mouse Formalin Model of Persistent Pain

Mice (Naïve, male C57B1/6) weighing between 22-30 g at the start oftesting were obtained from Harlan (Indianapolis, Ind.). All animals werehoused under a 12/12 h light/dark cycle with lights on at 0630. Rodentswere singly housed on solid bottom cages with corn cob bedding and hadaccess to food and water ad libitum. Animals were allowed to habituateto the vivarium for at least five days before testing was begun and werebrought into the testing room at least 30 minutes prior to dosing.Animals were pretreated with the appropriate test compound either byoral gavage or intraperitoneal injection at the desired pretreatmenttime (typically two hours before test onset) and then returned to theirhome cages. After dosing and at least 5 minutes prior to test onset,animals were acclimated to the individual testing chambers. At testtime, each animal was gently wrapped in a cloth glove with the left hindpaw exposed. A dilute solution of formalin (2%) in phosphate bufferedsaline was injected subcutaneously into the dorsal surface of the lefthind paw in a volume to 20 μL with a 30 g needle. Animals were thenplaced into the observation chambers and the behaviors were recorded for60 minutes following the formalin injection. A pain-like behavior wasdefined as licking and/or non-weight bearing of the injected hind pawnot associated with ambulation.

Statistical analysis was performed by analysis of variance (ANOVA), withpost-hoc analysis using the Dunnett post-hoc test compared to thevehicle group for any significant main effect. Data were represented asmean+/−standard error for each group.

Table 1 provides data for compounds exemplified in the presentapplication and priority document thereof, as representative compoundsof the present invention, as follows: compound name (as named usingChemDraw Ultra version 15.1; specific stereochemical designations suchas P, M, cis, and trans were added); and biological data includingin-vitro human Nav 1.7 IWQ data (IC₅₀ in uM) and Human CYP3A4 mRNAInduction at 10 uM percent of control (POC) (%), where available. Ex. #refers to Example No. ND means no data was available.

The potency of the compounds of the present invention were evaluated onhuman Na_(v)1.7 channels using the above described IonWorks Barracudaautomated electrophysiology platform that evaluates the ability ofcompounds to block sodium conductance through Na_(v)1.7 channels. Avoltage-protocol that prosecutes both state-dependent as well asuse-dependent inhibition was used as these modes of action are thoughtto be more relevant for the native state of Na_(v)1.7 channels in painsensing neurons in vivo.

The cytochrome P450 (CYP) is a well-known superfamily of enzymes thatare responsible for the oxidative and reductive metabolic transformationof medications used in clinical practice. In addition, the CYP enzymesare commonly associated with causing many clinically relevant drug-druginteractions. Of the CYP enzymes, CYP3A4 is not only the most prevalentCYP enzyme in the liver and intestine, but is responsible for metabolismand elimination of approximately 50% of marketed drugs. In addition,CYP3A4 activity can be induced (or increased) or inhibited (decreased)in response to administration of certain drugs, thereby affectingconcentrations of their own or certain concomitant drugs present in thebody. Typically, the induction of CYP3A4 is an undesired property of thedrug molecule as it can result in the reduction of parent drugconcentrations that may put patients at increased risk for lack ofefficacy or increased metabolite formation that can lead to safety risk.The CYP3A4 induction property was evaluated in an in vitro inductionassay where human hepatocytes were exposed to the test compounds atphysiologically relevant concentrations. Changes in the levels of CYP3A4were evaluated at the end of the experiment and compared against theincreased levels upon treatment with rifampin, a well-established CYP3A4inducer.

Representative compounds of the present invention show either favorableactivities against hNav1.7 IWQ or favorable human CYP3A4 induction dataas compared to Compound X, which is named1-(4-cyclopropyl-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide,having the structure below:

Compound X was exemplified in International Patent Publication No.WO2014201206A1, Example No. 1145. Preferred compounds of the presentinvention have both favorable activities against human Nav1.7 IWQ andfavorable human CYP3A4 induction data as compared to Compound X.

TABLE 1 BIOLOGICAL DATA Hu CYP3A4 hNaV1.7 mRNA IWB-U Induction Ex.# IC50(10 uM POC) Compound X 0.048 84.31 1 ND ND 2 0.025 ND 3 0.033 ND 4 0.01514.71 5 0.002 ND 6 0.011 83.89 7 0.007 16.35 8 0.005 10.51 9 0.002 ND 100.008 5.66 11 0.002 7.29 12 0.007 68.98 13 0.006 46.85 14 0.016 18.3 150.017 36 16 0.018 130.1 17 0.015 61.91 18 0.022 20.78 19 0.015 60.73 200.012 42.22 21 0.012 17.07 22 0.05 24.14 23 0.102 14.37 24 0.013 89.2625 0.037 18.57 26 0.08 14.58 27 0.104 48.14 28 0.054 60.29 29 0.03734.63 30 0.137 ND 31 ND ND 32 0.01 88 33 ND ND 34 0.028 69.54 35 0.0213.33 36 0.014 19.16 37 0.062 49.51 38 0.021 4.43 39 0.011 21.68 400.005 74.43 41 0.011 52.8 42 0.006 19.25 43 0.007 68.28 44 0.007 ND 450.008 36.685 46 0.008 6.6 47 0.008 19.64 48 0.01 110.2 49 0.01 64.94

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding.Those skilled in the art understand that changes and modifications maybe practiced within the scope of the appended claims. Therefore, it isto be understood that the above description is intended to beillustrative and not restrictive. The scope of the invention should,therefore, be determined not with reference to the above description,but should instead be determined with reference to the followingappended claims, along with the full scope of equivalents to which suchclaims are entitled.

All patents, patent applications and publications cited herein arehereby incorporated by reference in their entirety for all purposes tothe same extent as if each individual patent, patent application orpublication were so individually denoted.

What is claimed is:
 1. A compound of Formula (I):

an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof,or a pharmaceutically acceptable salt thereof; wherein: R¹ is asaturated or partially-saturated 4-membered monocyclic ring; or a 4-,5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring; wherein saidmonocyclic ring or bicyclic ring contains 0, 1, 2 or 3 N atoms and 0, 1,or 2 atoms selected from O and S; and wherein said monocyclic ring orbicyclic ring is substituted by 0, 1, 2 or 3 R^(1a) groups selected fromhydroxy, halo, C₁₋₈alk, C₁₋₈haloalk, —O—C₁₋₄alk, —O—C₁₋₈haloalk,—C(═O)C₁₋₄alk, —O—C(═O)C₁₋₄alk, —NH₂, —NHC₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk;R² is H, halo, C₁₋₆alk, or C₁₋₆haloalk; R³ is C₁₋₆alk, C₁₋₆haloalk,—O—C₁₋₆alk, or —CN; R⁴ is a 5- to 6-membered heteroaryl; Each of R⁶ andR⁷ is hydrogen; and Each of R^(5a); R^(5b); R^(5c); R^(5d); and R^(5e)is independently hydrogen or halo.
 2. The compound according to claim 1,an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof,or a pharmaceutically acceptable salt thereof, wherein said R^(1a) groupis selected from halo, C₁₋₈alk, —O—C₁₋₄alk, or C₁₋₈haloalk, wherein saidC₁₋₈haloalk is C₁₋₈fluoroalkyl.
 3. The compound according to claim 1, anenantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, ora pharmaceutically acceptable salt thereof, wherein said R¹ is acyclobutyl ring; or a 5-, or 6-membered bicyclic ring; wherein saidcyclobutyl ring or bicyclic ring contains 0 N, O, and S atoms; andwherein said cyclobutyl ring or bicyclic ring is substituted by 1, 2 or3 R^(1a) groups selected from F, —CF₃, —O—CF₃, or —C(CH₃)₃.
 4. Thecompound according to claim 1, an enantiomer, diastereoisomer,atropisomer thereof, a mixture thereof, or a pharmaceutically acceptablesalt thereof, wherein said R¹ is a cyclobutyl ring orbicyclo[1.1.1]pentan-1-yl ring; wherein each ring is substituted by 1 or2 F or —CF₃.
 5. The compound according to claim 1, an enantiomer,diastereoisomer, atropisomer thereof, a mixture thereof, or apharmaceutically acceptable salt thereof, wherein said R¹ is acyclobutyl ring substituted by 1 or 2 F or —CF₃.
 6. The compoundaccording to claim 1, an enantiomer, diastereoisomer, atropisomerthereof, a mixture thereof, or a pharmaceutically acceptable saltthereof, wherein said R¹ is a cyclobutyl ring substituted by 1 or 2—CF₃.
 7. The compound according to claim 1, an enantiomer,diastereoisomer, atropisomer thereof, a mixture thereof, or apharmaceutically acceptable salt thereof, wherein said R¹ is acyclobutyl ring substituted by 1 or 2 F.
 8. The compound according toclaim 1, an enantiomer, diastereoisomer, atropisomer thereof, a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein said R¹is a bicyclo[1.1.1]pentan-1-yl ring substituted by 1 or 2 F or —CF₃. 9.The compound according to claim 1, an enantiomer, diastereoisomer,atropisomer thereof, a mixture thereof, or a pharmaceutically acceptablesalt thereof, wherein said R² is H, fluoro, chloro, methyl, CF₃, CHF₂,or CH₂F.
 10. The compound according to claim 1, an enantiomer,diastereoisomer, atropisomer thereof, a mixture thereof, or apharmaceutically acceptable salt thereof, wherein said R² is H, fluoro,chloro, or methyl.
 11. The compound according to claim 1, an enantiomer,diastereoisomer, atropisomer thereof, a mixture thereof, or apharmaceutically acceptable salt thereof, wherein said R² is H orfluoro.
 12. The compound according to claim 1, an enantiomer,diastereoisomer, atropisomer thereof, a mixture thereof, or apharmaceutically acceptable salt thereof, wherein said R³ is methoxy.13. The compound according to claim 1, an enantiomer, diastereoisomer,atropisomer thereof, a mixture thereof, or a pharmaceutically acceptablesalt thereof, wherein said R⁴ is a 5-membered heteroaryl.
 14. Thecompound according to claim 1, an enantiomer, diastereoisomer,atropisomer thereof, a mixture thereof, or a pharmaceutically acceptablesalt thereof, wherein said R⁴ is a 6-membered heteroaryl.
 15. Thecompound according to claim 1, an enantiomer, diastereoisomer,atropisomer thereof, a mixture thereof, or a pharmaceutically acceptablesalt thereof, wherein said R⁴ is isoxazolyl, pyridazinyl, thiazolyl,thiadiazolyl, oxazolyl, or pyrimidinyl.
 16. The compound according toclaim 15, an enantiomer, diastereoisomer, atropisomer thereof, a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein said R⁴is isoxazolyl.
 17. The compound according to claim 1, an enantiomer,diastereoisomer, atropisomer thereof, a mixture thereof, or apharmaceutically acceptable salt thereof, wherein (a) each of R^(5a);R^(5b); R^(5c); R^(5d); and R^(5e) is hydrogen; (b) R^(5a) is F; andeach of R^(5b); R^(5c); R^(5d); and R^(5e) is hydrogen; or (c) R^(5c) isF; and each of R^(5a); R^(5b); R^(5d); and R^(5e) is hydrogen.
 18. Thecompound according to claim 1, an enantiomer, diastereoisomer,atropisomer thereof, a mixture thereof, or a pharmaceutically acceptablesalt thereof, wherein said R^(5a) is F.
 19. The compound according toclaim 15, an enantiomer, diastereoisomer, atropisomer thereof, a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein each ofR^(5a); R^(5b); R^(5c); R^(5d); and R^(5e) is hydrogen.
 20. The compoundaccording to claim 15, an enantiomer, diastereoisomer, atropisomerthereof, a mixture thereof, or a pharmaceutically acceptable saltthereof, wherein R^(5a) is F; and each of R^(5b); R^(5c); R^(5d); andR^(5e) is hydrogen.
 21. The compound according to claim 1, anenantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, ora pharmaceutically acceptable salt thereof, wherein said compound ofFormula (I) is selected from compounds of Formula (Ia), (Ib), or (Ic):

wherein each R^(1a) in said compounds of Formula (Ia), (Ib), or (Ic) isindependently fluoro, chloro, methyl, —O—CF₃, or CF₃.
 22. The compoundaccording to claim 21, an enantiomer, diastereoisomer, atropisomerthereof, a mixture thereof, or a pharmaceutically acceptable saltthereof, wherein said compound of Formula (I) is a compound of Formula(Ia); wherein said R^(1a) is CF₃; the cyclobutyl ring is a trans isomer;and R⁴ is isoxazolyl, pyridazinyl, thiazolyl, thiadiazolyl, or oxazolyl.23. The compound according to claim 21, an enantiomer, diastereoisomer,atropisomer thereof, a mixture thereof, or a pharmaceutically acceptablesalt thereof, wherein said compound of Formula (I) is a compound ofFormula (Ia); wherein said R^(1a) is cis CF₃; the cyclobutyl ring is acis isomer; R² is F; and R⁴ is isoxazolyl, pyridazinyl, thiazolyl,thiadiazolyl, or oxazolyl.
 24. The compound according to claim 21, anenantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, ora pharmaceutically acceptable salt thereof, wherein said compound ofFormula (I) is a compound of Formula (Ib); wherein each R^(1a) isfluoro; R² is F; and R⁴ is isoxazolyl, pyridazinyl, thiazolyl,thiadiazolyl, oxazolyl, or pyrimidinyl.
 25. The compound according toclaim 21, an enantiomer, diastereoisomer, atropisomer thereof, a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein saidcompound of Formula (I) is a compound of Formula (Ib); wherein eachR^(1a) is fluoro; R^(5a) is F; and R⁴ is isoxazolyl, pyridazinyl,thiazolyl, thiadiazolyl, oxazolyl, or pyrimidinyl.
 26. The compoundaccording to claim 21, an enantiomer, diastereoisomer, atropisomerthereof, a mixture thereof, or a pharmaceutically acceptable saltthereof, wherein said compound of Formula (I) is a compound of Formula(Ic); wherein each R^(1a) is CF₃.
 27. The compound according to claim 1,an enantiomer, diastereoisomer, atropisomer thereof, or a mixturethereof, or a pharmaceutically acceptable salt thereof, wherein thecompound is selected from: a)cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;b)trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;c)cis-(P)-1-(5-chloro-2-methoxy-4-((1S,3S)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;d)trans-(P)-1-(5-chloro-2-methoxy-4-((1S,3S)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;e)trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;f)trans-(P)-1-(5-chloro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;g)trans-(P)—N-(isoxazol-3-yl)-1-(2-methoxy-5-methyl-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;h)trans-(P)-1-(2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide;i)trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-2-oxo-N-(pyridazin-3-yl)-1,2-dihydroquinoline-6-sulfonamide;j)(P)-7-fluoro-1-(5-fluoro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;k)(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;l)cis-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;m)trans-(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethoxy)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;n)trans-(P)-5-fluoro-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)cyclobutyl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;or o) trans(P)-1-(5-chloro-2-methoxy-4-((1R,3R)-3-(trifluoromethyl)cyclobutyl)phenyl)-N-(oxazol-2-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.28. The compound according to claim 1, an enantiomer, diastereoisomer,atropisomer thereof, or a mixture thereof, or a pharmaceuticallyacceptable salt thereof, wherein the compound is selected from: a)(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;b)(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;c)trans-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;d)cis-(P)-1-(5-fluoro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;e)cis-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;f)trans-(P)-1-(5-chloro-4-(3-fluoro-3-(trifluoromethyl)cyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;g)(P)-1-(4-(3,3-difluorocyclobutyl)-5-fluoro-2-methoxyphenyl)-7-fluoro-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;or h)(P)-1-(5-chloro-4-(3,3-difluorocyclobutyl)-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide.29. The compound according to claim 1, an enantiomer, diastereoisomer,atropisomer thereof, or a mixture thereof, or a pharmaceuticallyacceptable salt thereof, wherein the compound is selected from: a)(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide;or b)(P)-1-(5-fluoro-2-methoxy-4-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)phenyl)-2-oxo-N-(pyrimidin-2-yl)-1,2-dihydroquinoline-6-sulfonamide.30. The compound according to claim 1, an enantiomer, diastereoisomer,atropisomer thereof, a mixture thereof, or a pharmaceutically acceptablesalt thereof, wherein said atropisomer is a P atropisomer.
 31. Apharmaceutical composition comprising a compound according to claim 1,an enantiomer, diastereoisomer, atropisomer thereof, a mixture thereof,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 32. A method of treating pain, cough, or itch, themethod comprising administering to a patient in need thereof atherapeutically effective amount of a compound according to claim 1, anenantiomer, diastereoisomer, atropisomer thereof, a mixture thereof, ora pharmaceutically acceptable salt thereof.
 33. The method according toclaim 32; wherein the pain is selected from chronic pain, acute pain,neuropathic pain, pain associated with rheumatoid arthritis, painassociated with osteoarthritis, pain associated with cancer, peripheraldiabetic neuropathy, and neuropathic low back pain.
 34. The methodaccording to claim 32; wherein the cough is selected from post viralcough, viral cough, or acute viral cough.
 35. A method of preparation ofa compound of Formula (A):

wherein R is halo; comprising: (1) reacting a trans olefin compound ofFormula (B):

wherein R is halo; and R¹ is C₁-C₆alkyl; with a UV light or near UVlight; to form a cis olefin compound (C); and (2) reacting said compound(C) with a chiral acid in an organic solvent to form said compound ofFormula (A).
 36. The method of claim 35, wherein said chiral acid is aphosphorus chiral acid.
 37. The method of claim 35 wherein said chiralacid is (S)-TRIP having the formula:


38. The method of claim 35, wherein said organic solvent isdichloromethane.
 39. The method of claim 35, wherein said R is bromo.40. The method of claim 35, wherein said R¹ is ethyl.
 41. The method ofclaim 35, wherein in reaction (2), a P atropisomer of said compound ofFormula (A) is selectively formed.
 42. The method of claim 35, whereinsaid compound of Formula (A) is used as an intermediate compound inpreparation of a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is asaturated or partially-saturated 4-membered monocyclic ring; or a 4-,5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring; wherein saidmonocyclic ring or bicyclic ring contains 0, 1, 2 or 3 N atoms and 0, 1,or 2 atoms selected from O and S; and wherein said monocyclic ring orbicyclic ring is substituted by 0, 1, 2 or 3 R^(1a) groups selected fromhydroxy, halo, C₁₋₈alk, C₁₋₈haloalk, —O—C₁₋₄alk, —O—C₁₋₈haloalk,—C(═O)C₁₋₄alk, —O—C(═O)C₁₋₄alk, —NH₂, —NHC₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk;R² is H, halo, C₁₋₆alk, or C₁₋₆haloalk; R³ is C₁₋₆alk, C₁₋₆haloalk,—O—C₁₋₆alk, or CN; R⁴ is a 5- to 6-membered heteroaryl; Each of R⁶ andR⁷ is hydrogen; and Each of R^(5a); R^(5b); R^(5c); R^(5d); and R^(5e)is independently hydrogen or halo; and Wherein a P atropisomer of saidcompound of Formula (I) is selectively formed.